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Spears CNS Exam 1 A
Headaches/Migraines Physiology
| Term | Definition |
|---|---|
| This type of Primary headache has a prevalence of 70% and affects both males and females and has BILATERAL localization. | TENSION headache |
| Treatment of Tension Headache consists of? | NSAIDS, Acetaminophen |
| This type of Primary headache has a prevalence of 0.1% effecting mainly males. Localization is noticed in the EYES (Hypothalamic circuits) Throbbing pain attributed to increased activity in hypothalamaic circuits. | CLUSTER headache |
| Treatment of Cluster Headache consists of? | Triptans, ergots, oxygen, 2-bro o-LSD (serotonigeric compound) |
| This type of Primary headache has a prevalence of 15% and affects females 2x more than males. Localization occurs UNILATERAL (one side of the face triggered by trigeminal neurons) | MIGRAINE |
| Treatment for migraines consist of? | Ergots, Tristan’s, mild opioids; Bblockers, TCAs, CCBs, botA (Botox A), CGRP modulators |
| This headache is severe intense throbbing pain with pulsating character mostly localized on one side of head | MIGRAINE |
| This headache has pain often around the eyes and pt may wake up often in the middle of the night | CLUSTER headache |
| This headache may be once or few times a week or continuous for several days | TENSION headache |
| Migraine headaches can have a frequency that is ________ or ___________ | episodic or chronic |
| Duration of Migraine headaches can last for how many hours? | 4-72 hours |
| ________ can worsen with exertion. Examples include: Hormones, alcohol, light, tobacco, sound, caffeine, mental stress, hunger, hypoglycemia, etc | Triggers |
| Migraine headaches involves AUTONOMIC symptoms such as: _____, ______/______ /______ _________ | nausea, light/sound/odor sensitivity |
| Migraine headaches may have unknown etiologies. This can include? | Rare, familial/individual hemispheric migraine; Aura, muscle weakness; CACNA1A, ATP1A2, or SCNA1 mutations |
| What are the 4 stages of migraines? | prodrome, aura (+/-), headache/attack, post-drome |
| what % of pts suffering from migraines may experience visual or sensory disturbance? | 30%; depends on what part of the brain is impacted, 1/2 of pt will experience an aura; |
| Migraine Visual or Sensory disturbances are caused by CSD. This stands for? | corticospreading depression |
| ________ pain syndrome with altered central neuronal processing and involvement of the trigeminovascular system. | NEUROVASCULAR |
| Central processing includes the? | brainstem, trigeminovascular system, and cerebral cortex |
| Brainstem contains the trigeminal centers (TCC) where we see activation of brainstem ______ | nuclei |
| Trigeminovascular system releases ______ causing inflammation, pain, etc | CGRP (Calcitonin gene-related peptide) |
| Cortical Spreading Depression consists of? | a wave of DEPOLARIZATION across the brain; Excitation in the cortex followed by depression of neural activity |
| With that depolarization wave, we get an increase in chemicals ____& ____ which is going to contribute to release of NT and also get more extracellular glutamate and K+. Remember that Glutamate is one of our primary excitatory NT so it will participate in activating several neurons | Ca2+; Na+ |
| CSD (Cortical Spreading Depression) will give massive increases in intracellular ___ & ___ | Ca2+; Na+ |
| CSD (Cortical Spreading Depression) will cause meningial inflammation and or astrogleal cells that can directly stimulate the activation of the _________ _____. | Trigeminal nerve |
| Know that CSD is ____ unique to migraines. It can also be seen in the development of seizures. | NOT |
| CSD can occur ____ or ____ an aura | with or without |
| The Trigeminovascular system consists of what components? | Trigeminal nerve (CN-V); Trigeminal ganglion; Trigeminocervical complex (TCC) |
| Normally CGRP would be released, it also activate as the release of serotonin and Norepi to try to modulate pain. But this pain signal that starts with activation of the trigeminal nerve and release of CGRP will stimulate these variety of 2nd order neurons that project to 2 important areas which are? | 1. Thalamus 2. Cortex |
| Thalamus is important because once that brain region is activated, it tells you that pain is occurring and has our body perceive that pain is occurring. Neurons that project to the ______ then correlate to where that pain is being felt | Cortex |
| The dorsal raphe nucleus releases? | 5-HT |
| The locus coeruleus releases? | NE |
| Once these meninges, usually dilated in migraine pain and have that increased inflammation--> releasing chemicals that activate the trigeminal nerve (CN-V)--> the TGN will feed into the _____ _______--> activating more neurons tat sends to other area of the brain. Some areas that are important are the _____ _____ ____ area that normally secreates 5-HT and also that locus Aurelius which secretes ___ | trigeminal ganglion; dorsal raphe nucleus; NE |
| 1. Migraine pain: Neurovascular Hypothesis--> Cortical spreading depresion +/- aura (wave of depolarization) leads to inflammation (vascular, nerve/glia, meningeal) and we get activation of ______ | TGN (Trigeminal nerve) |
| 2. Trigeminal ganglion rleeases Neuropeptidetes like ______ that also promote vasodilation in TCC (trigeminocervical complex) leads to? | 2nd order neurons that project to the thalamus and then to the cortex also become active and lead to the perception of migraine pain occuring |
| T/F: An aura is a wave of depolarization within the brain that always occurs prior to migraine pain. | False. because the wave of depolarization is defeined as the cortical spreading depression and aura doesnt always occur before the migraine attack. |
| Which tupe of primary headache typically involves the throbbing eye pain and occurs less often in women? | Cluster |
| Which are treu regarding the trigeminal ganglion in migraine pain? | A Pain fibers within the trigeminal ganglion can release CGRP; D. NT and Neuropeptides that cause vasodilation are released in the TCC |
| Acute Vs Prevetative migraine medications--> 1-3 | 1. decerase peptide release/ nerve activation/ inflammation 2. decrease pain NT 3. increase vasoconstriction |
| Pharmacotherapeutic approaches: Abortive vs Preventative measures. What is abortive? | ACUTE agents--> Anti-inflammatory, 5-HT receptor agonists (Ergotamines, Triptans); Dopaminergic receptor antagonists (Adjuvant); Narcotic analgesics; Calcitonin-gene-related peptide receptor antagonists |
| Pharmacotherapeutic approaches: Abortive vs Preventative measures. What is preventative? | PROPHYLACTIC agents--> Botulinium toxin; CGRP blockers (mAbs); CGRP antagonists |
| What is the role of Serotonin in the CNS? | Its able to inhibit or reduce pain modulation. |
| What is the effect of Serotonin in the CNS? | Nociception. Affects the vascular tone (Cerebral and Coronary) |
| Serotonin can act on the GI for Nausea/emesis at what receptor? | 5-HT3 |
| Serotonin can also affect? | Appetite; sleep/wake; Anxiety, depression, and mood; Aggresion and impulsivity |
| For pts with chronic migraine, they have consistently low ________. | Serotonin |
| Low 5-HT levels in chronic migraine pts could be attributed to? | A genetic component to either receptors or the Serotonin reuptake transporters. |
| High serotonin levels can occur during ______ ________ | migraine attacks. This could mean that a drop and then rapid increase is thought to contribute to the pain expressed in a migraine. |
| 5-HT1 subtype activation via __B/__D agonists. These receptors are expressed on the vascular smooth muscle. These increase _____ and decrease ______ | 1B/1D; Vasoconstriction; CGRP release |
| What is the difference of 1F agonist activation compared to 1B/1D agonist? | 1F has no vascular effects and see a decrease in CGRP and trigeminal pain perception. |
| SPEARS: "Difference with 1F agonist is that the serotonin 1F receptor isn't highly expressed on the vascular tissue, so you get less of the ______ effects by you do see a reduction in CGRP at the ________ ______ and decreased pain perception" | vasoconstriction; trigeminal nerve; |
| Effects of CGRP: CGRP is a potent ___________ increasing blood flow to the regions where its released. This contributes to the dilation of the _________ and the vessles aroind those that contribute to increased inflammation and activation of these pain cascapdes in the trigeminal area. | vasodilator; meninges |
| CGRP pain signaling effects can be seen in the CV system, with neuroinflammation, in the reproductive, pulmonary and GI system impacting ________ and _______ | motility and secretion |
| CGRP is not elevated in ______ headache and is more associated with migraine pain | Tension |
| High CGRP levels in migraine pts was seen in clinical trials that showed? | unchanged CGRP levels in tension headaches vs healthy pts. |
| CGRP blockers are effective antimigraine therapeutic agents. What are their 3 major effects? | Vascular effects (promote vasoconstriction) Immune cells (reduce activity of immune cells) GI symptoms (impact and reduce GI symptoms) |
| MOA of NSAIDS? | COX-1/COX-2 inhibtion, decrease prostoglandins |
| Which NSAIDS are more COX-1? | Aspirin, Naproxen |
| Which NSAID is more COX-2? (hint: not celebrex) | Diclofenac |
| MOA of Dexamethasone? | GR agonist (low MR affintiy (meaning reduced Na+ retention); PLA2/COX-2 inhibition, decrease AA/PG |
| NSAIDS and Glucocorticoids (Dexamethasone) are effective for what tension headaches & ____ to ______ migraines | mild to moderate |
| Acute Migraine medications: what are the 2 Ergotamines we have that act as 5-HT agonists? | Ergotamine tartrate; Dihydroergotamine |
| What is the MOA of Ergotamines? | NON-SELECTIVE, 5-HT receptor partial agonists; Alpha-adrenergic receptor agonist |
| Acute Migraine medications: what are the 7 triptans that act as 5-HT agonists? | Alptriptan; Electriptan; Frovatriptan; Naratriptan; Rizatriptan; Sumatriptan*; Zolmitriptan |
| MOA of Triptans? | PARTIAL, SELECTIVE 5-HT 1B/ 1D agonist (1 impact is that it can reduce the release of CGRP--> less stimulation of those 2nd order neurons that project from the trigeminal system to the thalamus and cortex |
| Ergotamines and Triptans have similar uses, what are they used for? | acute migraine pain via vasoconstriction; decrease CGRP releease; Post-partum bleeding (ergots) |
| AE of Ergotamines are? | N/V (DA/5-HT activity); Vasospasm, Rebound headache with overuse; nephrotoxicity; erbot toxicity (seizures, fingertip necrosis) |
| Of note for Ergotamines? | Ergot alkaloids can block DA and/or adrenerigic receptors (varies by structure); CI in pregnancy; Serotonin syndrome |
| T/F: Ergotamines and Triptans can be given together? | NEVER, don't want to cause serotonin syndrome. |
| AE of Triptans are? | Paresthesia, dizziness, coronary vasoconstriction, serotonin syndrome from combined use of triptans and ergots, MAOIs, SSRIs, or SNRIs |
| Of note for Triptans? | Caution use with CV issues or cerebrovascular disease. CI in ischemic heart disease and coronary artery vasospasm. Other agents may be preferred (increase preterm births) *Sumatriptan can be available with Naproxen |
| Acute Migraine medications: What is our 1 ditan drug? | Lasmiditan |
| MOA of Lasmiditan? | SELECTIVE 5-HT-1F agonist |
| Indication for Lasmiditan? | decreases Acute migraine pain; trigeminal activation without affecting vasoconstriction |
| AE of Lasmiditan? | Dizziness, vertigo, nausea, paesthesia |
| Of note of Lasmiditan? | Fewer adverse CV complications compared to Triptans. *Safer for pts with cardio problems that suffer from migrains |
| Difference in targeting 1B/1D to IF? | Vasoconstriction |
| Ergot derivatives compared to Full agonists. What is the differnece? | The ergot derivatives dont cause as much contraction as our endogenous full agonists. Potency is different with more potency but less effectiveness seen with ergot derivatives (ERG and DHE) due to being PARTIAL AGONIST |
| Acute Migraine Medications: CGRP antagonists include--> | Ubrogepant, Rimegepant*, Zavegepant (nasal): |
| MOA of CGRP receptor antagonist--> | COMPETITIVE, reversible blockade of CGRP receptor |
| Uses for CGRP receptor antagonists—> | Acute migraine pain |
| AE for CGRP receptor antagonists—> | Nausea/ skin rash, hypersensitivity |
| Of note for CGRP receptor antagonists—> | Shorter 1/2 life than mAbs; also prophylactic |
| Dopamine receptor antagonists include? | Metoclopramide |
| MOA of Dopamine receptor antagonists is? | Dopamine-2 (D2) receptor antagonist |
| Usees for Metoclopramide? | adjunct therapy to increase Tristan/NSAID oral absorption; antinausea/emetic; GERD treatment |
| AE For Metoclopramide? | Drowsiness, fatigue, restlessness, insomnia, anxiety, hyperprolactinemia, dyskinesias |
| Of note for Metoclopramide? | Box warning: TARDIVE DYSKINESIA |
| Our mild narcotic with an MOA of MIXED OPIOID, MOR partial agonist/KOR agonist. Name the drug? | Butorphanol |
| Uses for Butorphanol? | analgesia |
| AE of Butorphanol? | opioid SE; Sedation; Abuse liability |
| Of Note for Butorphanol? | Avoid with other CNS depressants |
| Which acute migraine to selectively stimulates 5HT1B receptors? | Eletriptan |
| The use of a triptan drug as an “abortive (Acute) migraine to is important to… | -stimulate cerebral vasoconstriction -To inhibit vasodilation -To reduce CGRP levels in the TCC |
| Botulinum Toxin A is part of the neurotoxin Drug class. MOA? | SNARE protein cleavage; inhibits vesicular release (ACh, CGRP) *cleave SNARE which prevents vesicles from fusing to the plasma membrane and releasing their NT; in the presence of Botox, less CGRP being released |
| Botulinum Toxin A is part of the neurotoxin Drug class. Uses? | Migraine prophylaxis; Muscle spasms; cosmetic, skin rejuvenation |
| Botulinum Toxin A is part of the neurotoxin Drug class. AE? | Muscle weakness, flaccid paralysis; death |
| Botulinum Toxin A is part of the neurotoxin Drug class. Of Note? | RTI, muscle weakness, urinary incontinence, falls, fever |
| CGRP receptor antibodies consist of 1 drug. Name and MOA? | Erenumab; Monoclonal antibodies for CGRP receptor; REVERSIBLE |
| Name the 3 CGRP Ligand antibodies and the MOA? | Fremanezumab; Galcanezumab; Eptinezumab; Monoclonal antibodies for CGRP ligand |
| Name the 2 CGRP receptor antagonists (Non-biologics) and their MOA? | Atogepant; Rimegepant; Small molecule CGRP receptor blockers |
| What is the indication for CGRP Receptor antibodies, CGRP ligand antibodies, CGRP receptor antagonists (non-biological)? | Migraine prophylaxis |
| AE of CGRP receptor antibodies and CGRP Ligand antibodies? | Nausea, diarrhea, antibody development, hypersensitivity |
| Of Note CGRP Receptor antibodies includes? | Rapid association; slow disassociation, long 1/2 life |
| Of note for CGRP ligand antibodies? | Cluster headaches (galcanezumab |
| Of note for both CGRP receptor and ligand antibodies—> | Avoid with other monoclonal antibodies and immunosuppressants (i.e, belimumab, natalizumab, tacrolimus) |
| Botox cleavage of SNARE proteins includes? | 3 snare proteins (Synaptobrevin, Syntaxin, and SNAP-25, just know Botox will cleave SNARE proteins and so when these SNARE proteins are not engaged, the vesicle is unable to fuse with the plasma membrane and releasing their NT its contents. So CGRP would remain in the vesicle and less of it would be released into the trigeminal nerve system |
| Beta blockers mentioned in CNS include which ones and MOA? | Metoprolol, Propranolol, Timolol MOA: Non-selective B-AR antagonist; Blocks B2 induced-vasodilation |
| Uses of Beta Blockers includes? | Vasoconstriction, Antihypertensive |
| TCA’s mentioned in CNS includes only which drug and MOA? | Amitriptyline; MOA: blocks NET/SERT reuptake; increasing NE and 5-HT |
| Uses of TCA’s include? | Analgesia; Antidepressant |
| CCB’s mentioned in CNS includes which drug and MOA? | Verapamil; MOA: inhibits slow voltage Ca2+ channels |
| Uses of CCB’s includes? | Anti-inflammatory; anti-hypertensive |
| Anticonvuslants mentioned by Spears includes what 2 drugs and MOA? | Valproate and Topiramate; MOA: Na+ channel inactivation and other mechanisms |
| Uses of anticonvulsants includes? | Anti-inflmmatory; Anticonvulsants |
| All Beta blockers, TCA’s, CCB’s, and Anticonvulsants mentioned can be used for? | Migraine prophylaxis; Inhibition of CSD |
| Summary of CGRP Targets for Migraine therapies—> difference between Ergots and Tristans—> | Triptans—> reduce CGRP release; Ergots (non-selective and stimulate others. 1B/1D (expressed on trigeminal nerve but remember that 1B and 1D are also expressed on vascular tissue as well. |
| Triptans and ergots try to ______ the effects of 5-HT to inhibiit release of CGRP | mimic |
| The role of Erenumab (remember its an Anti-CGRP receptor antibody) is to: | sequester or binds to the receptor itself to prevent the interaction of CGRP with the receptor |
| Zumab’s role (Anti-CGRP antibody) is to | bind to the ligand and prevent ligand from interacting with the receptor |
| _____ will block the binding site for CGRP to inhibit CGRP activity. So in the presence of these compounds, you can get less vasodilation or promoting more vasoconstriction | Gepants |
| All prophylactic medications for migraines are? | Botulinum Toxin A (Neurotoxin); Erenumab (CGRP receptor antibodies); Fremanezumab, Galcanezumab, Eptinezumab (CGRP Ligand antibodies); Atogepant, Rimegepant CGRP receptor antagonist (non-biologics) |
| Rimegepant (CGRP receptor antagonist can act as both an ______ and a prophylactic medication | acute |
| Prophylactic migraine medications also include: | BB, TCA, CCB, and Anticonvulsants |
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