Exam 2 Flashcards
What is epilepsy?
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.
What are the 3 types of seizures?
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
What are the different types of seizures included in the generalized seizure category?
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.
What are the two main ways anti-seizure medications help those with epilespy?
- Acute seizure termination
- Long-term prophylaxis
What type of drug is Carbamazepine?
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).
What is the difference between the selective Na+ channel blockers and the non-selective Na+ channel blockers?
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.
What is the only type of seizure that carbamazepine works well for?
Focal seizures
How does carbamazepine effect CYP450 enzymes in the liver?
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.
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?
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.
What anti-seizure drug has the broadest range of activity among all seizure types?
Valproic acid. This drug works well in treating tonic-clonic, absence, status epilepticus, and focal.
What is a major side effect of valproic acid use in pregnant people?
Can induce neural tube defects that manifest as spina bifida and different variations of improper neural tube closure.
What is the MOA of valproic acid?
This drugs blocks Na+ channels and thalamic Ca2+ channels. Blocking these channels prevent neuron depolarization therefore decreasing its hyperexcitability.
What is the drug Topiramate?
This is newer anti-seizure drug with less issues. It is only available for oral use.
What is the MOA of Topiramate?
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.
What are the seizure types that respond best to Topirmate?
Tonic-clonic and focal seizures respond best.
What are important side-effects of Topiramate?
Associated with cleft lip/palate and weight loss.
What is the drug ethosuximide used for?
This drug has a narrow range of use for absence seizures in children.
What does an absence seizure look like on an EEG?
What is seen is a hyper-synchronized rhythm that is generated by a circuit where cortical and thalamocortical relay neurons repetitively stimulate each other.
What is the MOA for Ethosuximide?
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.
What is ethosuximide indicated for?
It is only indicated in absence seizures in children.
What is the drug Levetiracetam?
Levetiracetam is a synaptic transmission modulator unlike the other anti-seizure medications that act on ion channels.
What are the main types of seizures that Levetiracetam is used for?
Levetiracetam is best used in tonic-clonic, status epilepticus, and focal seizures.
Explain the process of synaptic vesicles releasing neurotransmitters into the synaptic cleft.
- 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.
What is the MOA of levetiracetam?
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.
What is the most prominent side-effect of Levetiracetam?
Mood swings, agitation, irritability especially in children.
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
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.
What is chronopharmacology?
This is the study of drug actions in the context of the natural body rhythms.
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.
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.
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.
What are the 3 different types of molecular clocks?
- Post-translational phosphorylation clock- 3 algae proteins in a test tube cyclically oscillating phosphorylating ATP on a 24 hr cycle.
- Gene expression oscillator network- Handful of genes drive this rhythm within mammals. Seen within cells that have a nucleus
- Redox clocks- in cells that have no nucleus like RBCs.
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
What is the primary time cue/ zeitgeber?
Light
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.
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.
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.
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.
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.
What different aspect of pharmacokinetics is affected by the circadian rhythm?
- Gastric pH which effects absorption
- Xenobiotic metabolism pathway meaning how exogenous things are broken down
- Excretion in the liver and kidney like changes in renal blood flow, GFR, reabsorption of drugs and more.
The more __________ a drug is, the more likely ________ is to matter.
Dangerous;
Rhythmicity
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.
Explain the ultradian rhythm of the sleep cycle.
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.
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.
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.
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.
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.
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.
What are the different risk factors for a stroke?
Risk increases with age
Smoking
High BP
High Cholesterol
Obesity
Diabetes
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.
What is the FAST acronym for stroke?
F- face drooping
A- arm weakness
S- speech difficulty
T- time to call 911!
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.
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!!!!!!
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.
What are some issues that can arise when using tPA to treat an ischemic stroke?
It can cause excessive bleeding, pulmonary embolism, or reembolization.
Can tPA reverse the damage done by a stroke?
No, it can only break down the clot and prevent further brain damage.
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.
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.
What type of disabilities appear after a stroke?
Disabilities could include paralysis, motor control issues, pain, aphasia, issues with memory, and more.
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
What are the two types of headaches?
Primary
AND
Secondary- headache is secondary to underlying pathology like meningitis, etc
What are the 3 types of primary headaches?
- Tension- Most common type of headache. It can last a very long time. Pain is mild to moderate.
- 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. - Cluster- Very low prevalence of this. Very odd type of headache that comes on with different seasons.
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.
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
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.
What is etorphine used for?
This is mainly a veterinary agent as it is 1000x more potent than morphine.
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.
Explain the connections that occur with an injury stimulus happens.
- Finger injury!
- Pain sensed by primary afferent sensory neuron. Its cell body lives in the dorsal root ganglion next to spinal cord.
- Pain travels down primary afferent sensory neuron via action potentials to the cell body in the dorsal root ganglion
- From the cell body, the axon carries it into the actual spinal cord.
- Primary afferent sensory neuron and dorsel horn projection synapse together at the dorsal horn.
- The dorsal horn projection neuron then carries the pain signal to the brain.
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.
What is the MOA for the TCA, Amitriptyline?
Inhibits breakdown of 5HT and NE. Helps neuropathic pain the same way the SNRIs do.
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.
What are the 4 different types of local anesthesia?
Topical
Infiltration
Nerve block
Epidural or spinal
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.
