midterm Flashcards
structures/functions of brainstem
pons, medula, midbrain
survival reflexes (BP, HR, CO0
structures and functions of the Diencephalon
thalamus and hypothalamus
homeostasis (thermoregulation), control of the autonomic nervous system, survival behaviours (aggressive, defensive, consummatory, reproduction)
pituitary hormonal regulation
structures and functions of the limbic system
hippocampus and amygdala
judgement, inhibition, memory and attention
basal ganglia functions
regulate motor control - the contraction of opposing muscles
oligodendrocytes
cells that myelinates CNS nerves
1 can do 50 axon segments
cerebellum functions
coordinates voluntary movement, maintain balance, eye movement
cerebral cortex functions
controls sensory and motor activity, language, thought, idea formation, longterm memory storage
schwann cells
myelinate PNS nerves
microglia
the immune (phagocytic) cells of the brain
astrocytes
provides substrates for neurons - clean up after neurons. these cells do not overlap. one of them can unsheath over 100,000 synapses, and can stimulate adjacent astrocytes leading to signal propogation
what is special about astrocytes
they are polarized
describe the physical, chemical, and physiochemical characteristics of the blood brain barrier
physical - no pores/fenestrations - tight junctions. layers of astrocyte and pericyte endfeet provided an added layer of protection
chemical - 5x the amount of mitochondria, which are high in enzymes
physiochemical - lots of plasma protein binding
difference between neurotransmitters and neuromodulators
neurotransmitters are only active for a couple milliseconds, whereas neuromodulators can last multiple seconds
neuromodulators act on receptors distant from their release site, they alter neurotransmission
neurotransmitters act on ionotropic receptors (those that directly modify ion channels)
describe the steps of neurotransmission
- DNA/RNA/Protein synthesis triggers axoplasmic transport
- neurotransmitters are made and stored
- an action potential occurs which depolarizes membranes and opens calcium channels
- neurotransmitters are released and couple to their receptors
- NT removed from synapse either from reuptake or metabolism
major source of NE
locus coeruleus
main roles of NE neurotransmission
- central response to stress
- modulatory role in focus, attention, and performance
- activity in RAS, limbic system, hypothalamus
major source of dopamine
ventral tegmental area - temporal lobe output
major roles of dopamine neurotransmission
extrapyramidal motor system (parkinsons)
limbic system (psychosis and affective disorders)
hypothalamus (reward and pleasure systems)
chemoreceptive trigger zone
major source of serotonin
Raphe nuclei
major source of acetylcholine
nucleus basalis
acetylcholine is majorly involved in this system, causing parkinsins
extrapyramidal motor system
major source of histamine
tuberomammillary nucleus (hypothalamus)
_____ is the major excitatory neurotransmitter
glutamate
true or false - excess glutamate can cause neurodegeneration
true
______ is the main inhibitory neurotransmitters
GABA
GABA is mainly involved in this system, disregulation in which can cause parkinsons and huntingtons
extrapyramidal motor system
substance P is mainly located in
spine and thalamus
endorphins/enkephalins/dynorphins are mainly involved in which system
the limbic system, and analgesia
extrapyramidal tracts are involved in
the fine regulation of motor activity
they direct the stimulation and inhibition of antagonistic muscle groups to allow for smooth and coordinated movement
this neurotransmitter is responsible for inhibition in the extrapyramidal system
dopamine mediates inhibition in the extrapyramidal system
this neurotransmitter is responsible for excitation in the extrapyramidal system
acetylcholine mediates excitation in the extrapyramidal system
parkinsons disease is a neurodegenerative disease caused by the death of …
dopamine neurons in the substantia nigra and dopamine nerve terminals in the neostriatum (dopamine defeciency)
main symptoms of parkinsons disease
akinesia - inability to initiate movement
bradykinesia - slow or shuffling movement
cognitive and mood symptoms (dementia, depression)
- muscle rigidity, tremor at rest, mask like emotionless face, jerky movements
symptoms of parkinson’s disease only occur after death of about ____% of dopamine neurons
80%
Since dopamine cannot cross the BBB, dopamine replacement therapy for Parkinson’s disease uses
Levodopa - actively transported across the BBB and taken up by surviving dopamine neurons to restore the balance between dopamine and acetylcholine, allowing for normal Extrapyramidal motor function
adverse effects of levodopa for PD
increases NE and E in the periphery causing increases SNS activity - hypertension, tachycardia, arrhythmias
chemoreceptive trigger zone dopamine receptor stim = nausea and vomiting
psychosis - dopamine overstim in mesolimbic areas
inhibit prolactin release
dyskineas - dopamine overstim in motor areas
insomnia and anxiety - NE receptors in RAS and Limbic systems
why are carbidopa and benserazide used in combination with levodopa to treat PD
they reduce or prevent peripheral side effects by inhibiting aromatic amino acid decarboxylase
why are entacapone and tolcapone used in combination with levodopa to treat PD
they stabilize L-dopa plasma concentrations by inhibiting peripheral COMT which metabolizes L-dopa before it crosses the BBB - allows for a reduced dose of L-dopa
How are selegiline and rasalgiline used to treat PD
they are MAO-B inhibitors which inhibit the breakdown of Dopamine, lowering the dose necessary for L-dopa as well as reducing the accumulation of toxic by products (oxygen radicals) produced by L-dopa metabolism
while Bromocriptine, pramipexole, rupinirole, and rotigotine are all
dopamine receptor agonists which can be used to improve symptoms in combo with L-dopa. the latter three are newer and have less side effects. Because they use a blanketed approach to dopamine distribution, they have more side effects in general (like psychosis) and are likely used in later stages
why do anticholinergic drugs work for PD? give two examples
because the disease is due to a lack of dopamine causing there to be an imbalance of the NT involved in the extrapyramidal system (dopamine inhibition, ACh excitation) meaning there is too much ACh leading to excess GABA release
Benztropine, Trihexyphenidyl
negative symptoms of schizophrenia
affective flattening (unchanging facial expression)
Avolition apathy - lack of hygiene, no work ethic
positive symptoms of schizophrenia
hallucinations, delusions, bizarre behaviours
what is the dopamine hypothesis of schizophrenia
the theory that dopamine receptor overstimulation may be the cause of the positive symptoms of schizophrenia since amphetamines can cause psychosis (and they act on DA receptors)
this can be treated with DA receptor antagonists - but they only reduce the positive symptoms
atypical vs typical antipsychotics
The typical antipsychotics are DA antagonists only, whereas the atypical ones are also serotonin antagonists
Atypical antipsychotics reduce both positive and negative symtpoms, whereas typical antipsychotics tend to only reduce positive ones, and may exacerbate negative symptoms
both are effective but the atypical ones have better side-effect profiles
why are long-acting antipsychotics used
these are doses that are formulated in oil for deep IM injection to use for non-compliant patients. they have an increased risk of extrapyramidal symptoms, PD, and neuroleptic malignant syndrome
list three typical antipsychotics in order of decreasing potency
haloperidol, zuclopenthixol, chlorpromazine
what is special about the antipsychotic haloperidol
it is very selective dopamine antagonist with a high potency, so its good at treating the positive symptoms but it can aggravate the negative symptoms
what are the common side effects of the typical antipsychotics haloperidol, zuclopenithixol, and chlorpromazine
extrapyramidal motor symptoms, hyperprolactinemia, tardive dyskinesia
chlorpromazine may cause chemoreceptor trigger zone issyes
how is chlorpromazine different than haloperidol and zuclopenithixol
while it is a DA antagonist like those two, it is also an alpha-adrenergic antagonist, muscarinic antagonist, and histamine antagonist so it has a host of other side effects (postural hypotension, constipation, sedation, sedation, itching)
common symptoms of the atypical antipsychotics
weight gain, hyperglycemia and lipid abnormalities
what are the four atypical antipsychotics
clozapine (agranulocytosis - bone marrow supression)
risperidone
olanzapine (may halt progression of schizophrenia)
quetiapine (cheaper)
four major extrapyramidal motor system symptoms of antipsychotics
acute dystonia - rapid onset of spasm of tongue/face/neck - can be fixed with benztropine
akathisia - inability to stay still causing extreme distress - lower drug potency
pseudoparkinsonism - bradykinesia, rigid, variable tremor, shuffling gait (fix with benztropine)
perioral tremor - rabbit like movements of mouth and face
what is neuroleptic malignant syndrome
a condition induced by high potency neuroleptics resulting in fever, muscle rigidity, unstable blood pressure, and lactic acidosis caused by a MASSIVE DA BLOCK
how do you treat neuroleptic malignant syndrome
stop the neuroleptics, hydrate and cool down, use muscle relaxant like dantrolene and DA agonist like bromocriptine
the symptoms of Alzheimers can be described by the 4A’s and one D, which are:
anterograde amnesia
aphasia
apraxia (inability to perform tasks)
agnosia (inability to recognize common objects)
Disturbance in executive functioning
common symptoms of all dementias include
short term memory loss, impaired memory retrieval, unstable or inappropriate emotions
in later stages - motor function impairments
neuropathology of AD
loss of cholinergic neurons in the nucleus basalis of meynart, but this may be preceded by a loss of NE neurons in the locus coeruleus
in any case the loss of neurons precedes the appearance of symptoms by years
describe the different amyloid precursor proteins APP
sAPPα = the good one - neuroprotective, cleaved by α-secretase
sAPPβ = bad one - stimulates axonal pruning and neuronal cell death. cleaved by β-secretase
how is aducanumab used in AD treatment
it is used to clear plaques using IV infusion of anti-amyloid antibodies
while it can delay the clinical decline, the plaques are not the causative agent of the disease
because AD is caused by a ____ deficiency, one common treatment method is the use of ____ inhibitors
deficiency in ACh, so use AChE inhibitors
list the three AChE inhibitors used to treat AD, and the special notes for each
Donepezil - reversible AChE inhbitor with high bioavailability and 40% PP binding
galantamine - same as above, much less PP binding (18%), can be used as a sleep enhancer
Rivastigimine - a Butyrylcholinesterase and AChe inhibitor which BYPASSES CYP pathways to lower drug drug interactions
patients who have AD but cannot tolerate AChE inhibitors may be treated by
Memantine / nitromemantine- a noncompetitive low affinity antagonist of NMDAR (glutamate) and nicotinic ACh receptors - slows calcium influx caused by glutamate overexcitation, slowing neuronal death
list two anti-beta-amyloids used for AD
valproic acid - reduces beta amyloid deposits in mouse models
Pioglitazone - stimulates amyloid clearance and reverses cognitive deficits in mouse models
what separates major depressive disorder from depressive disorders
the presence of cognitive symptoms such as inappropriate negative thoughts, pseudodementia, hallucinations
monoamine oxidase a enzymes located in / has a high affinity for
neurons liver and GI TRACT
high affinity for serotonin
monoamine oxidase b
neurons liver and PLATELETS
high affinity for dopamine
how are monoamine oxidase inhibitors used for the treatment of depression - give an example of a drug
moclobemide - MAO-A selective inhibitor which will increase 5HT and NE content in the brain without causing the wine-cheese effect
how do tricyclic antidepressants work and give an example
these are drugs which increase the concentration of NE and serotonin, then are metabolized into a drug which is specific for NE reuptake inhibition
ex Imipramine which gets metabolized to Desipramine
- also have low affinity for adrenergic and muscarinic receptors leading to possible side effects of postural hypotension and memory impairment
what are SNRIs and give an example
serotonin and NE reuptake inhibitor which does not get metabolized to another active form, and lacks affinity for other receptors
ex - Venlafaxine
fluoxetine
SSRI - only inhibits serotonin reuptake, lacks affinity for NT receptors
but is a Cytochrome CYP 2D6 inhibitor which can cause fatal drug interactions with narcotics and beta blockers
example of an atypical antidepressant
Mirtazapine - a presynaptic alpha2 receptor antagonist which causes increased release of serotonin and NE
T/F - in antidepressants, the direct, acute effects are not the same as the therapeutic action
true - these drugs take weeks for clinical improvement to be noticeable but may cause side effects before then
this mood stabilizer, used to treat bipolar disorder is capable of stopping a manic episode, preventing future ones and presents a slight antidepressant effect
lithium - prevents feedback inhibition of serotonin reuptake and enhances glutamate reuptake
main concern with lithium
low therapeutic index – the difference between the toxic and effective dose is very small
while both Carbamazepine, valproic acid, and lamotrigine are used to treat BPD by decreasing voltage gated sodium channels while potentiating GABA receptors, valproic acid is more suited for
those patients with rapid manic-depression cycles
valproic acid also may increase BDNF levels to help depression
why is lamotrigine unique for the treatment of BPD
it is good at treating the depressive phase, whereas other sodium channel blockers (carbamazepine and valproic acid) are not
how do atypical antipsychotics (clozapine, risperidone, olanzapine) aid in the treatment of BPD
they can treat acute mania, suppress delusions, and other psychotic disorders
what is combination therapy for BPD
an atypical antipsychotic (olanzapine) with fluoxetine
what class of drugs seems best suited to treat BPD
anticonvulsants, lithium is not well tolerated by most
anxiety performance graph is this shape
inverted U
what are some uses for Benzos
anxiolytic
hypnotic
analgesic
anticonvulsant
muscle relaxant
neurochemical effect of benzos
enhance GABA receptor binding (this being an inhibitory neurotransmitter) leading to increased calcium influx causing inhibition of APs
overtime - down regulation of benzo receptors but upregulation of NE, 5HT receptors
Flumazenil is a selective GABA antagonist used to treat overdoses of this drug (for which it is a competitive inhibitor)
benzos
two examples of benzos and their relative potencies and half lives
Diazepam has low potency but a really long half life. It is more often an anxiolytic.
Triazolam has high potency but a very short half life. It is more often a hypnotic.
withdrawal induces the opposite of the therapeutic effects of a drug, and will last until
receptor densities return to normal (pre-tolerance) state
this atypical anxiolytic is a selective partial ahgonist at serotinin A receptors, reducing anxiety without hypnotic, anti-convulsant, or muscle relaxant effects. It is good because it does not have drug drug interactions with alcohol or narcotics, but it takes weeks to work
Buspirone
this atypical anxiolytic is a beta blocker often used for performance anxiety to suppress somatic and ANS symptoms
propranolol
what are the three types of sleep disorders
poor sleep hygiene
psychophysiologic insomnia - hyperarousal and escalating anxiety
paradoxical insomnia - normal sleep demonstrated but person feels like they slept bad
what are the three sleeping medications we discussed
zolpidem - short half life and does not terribly affect EEG but still not great
Ramelteon - CNS depressant acting on melatonin receptors with minimal side effects (endogenous response)
Melatonin - endogenous, next to no side effects
what are the two types of seizures and how does the type affect treatment options
partial or focal onset - may have auras - almost all (not ethosuximide) anti-epileptic drugs can stop these kinds of seizures
generalized onset - happens all over the brain all at once - tonic /clonic seizures where you fall and flail or the spaced out kind - treatment for these is more limited
ethosuximide is an AED which is unique in that it can treat
absence seizures, its mechanism of action is blocking calcium channels in the THALAMUS
Valproate (valproic acid) is an AED which is unique in that it works by 4 different mechanisms of actions. What are they?
prolong refractory period of NA channels (at high doses)
Potentiate GABA (inhibitory NT) mechanisms by increasing Cl channel opening frequency
Block Calcium channels in the thalamus - which is indicated in absence seizures
increase K+ channel permeability
what are the six mechanisms of action for AEDs
prolong refractory period of sodium channels
potentiate GABA mechanisms (inhibitory NT to reduce excitation)
block calcium channels which stops NT release
block glutamate receptors (excitatory NT)
open Potassium channels (hyperpolarize neurons to reduce AP firing)
stop exocytosis
phenytoin is an AED which works by increasing the refractory period of Na channels - but it is special in that it displays
zero order kinetics so the concentration rapidly increases when enzymes are saturated
the AEDs Phenytoin, Carbamazepine, and oxcarbazepine have worrying pharmacokinetic side effects because they are
P450 enzyme inducers, so they could have toxic side effects
Carbamazepine can induce its own metabolism
how do the AEDs Lamotrigine and Valproic acid interact
lamotrigine is metabolized by glucuronic acid conjugation, and VPA decreases glucuronidation, so it doubles the lamotrigine halflife
what are the two main classes of drugs which work as AEDs by potentiating GABA systems (increasing inhibitory NT)
Benzos (lorazepam, diazepam, clobazam) and Barbiturates (phenobarbital)
benzos are not ideal for long term use in general because of tolerance and withdrawal, but these two are used as AEDs which potentiate GABA Nt
clobazam and clonazepam
barbiturates like Phenobarbital are primarily used as AEDs in this demographic
neonates - phenobarbital withdrawal can cause prolonged seizures even in non-epileptics
gabapentin and pregabalin are Ca channel blocking AEDS which block this type of calcium channels
presynaptic - decrease glutatmate release
felbamate, topiramate, and perampanel are AEDs which work via
blocking glutamate release
the two AEDs which work by increasing potassium channel permeability
VPA, ezogabine
which AED works by exocytosis antagonism
levetiracetam
which AEDs are not metabolized by the liver
gabapentin, pregabalin, vigabatrin, levetiracetam
the two common classes of natural stimulants are
methylxanthines (caffeine) and ephedrine
Caffeine
xanthine based natural stimulant which easily crosses the BBB (both water and lipid soluble) - metabolized by CYP1A2 with a half life of 6 hours
describe the mechanism of action of the synthetic stimulant amphetamine
stimulates the release and blocks the reuptake of NE and DA (and to a lesser extent - serotonin)
inhibits MAO - enzyme which degrades NE and serotonin a(at high conc)
agonist of NE receptors
stimulant drugs are used to treat what? How do most of them work
ADHD, Obesity, narcolepsy
increasing availability of NE and DA
this stimulant is the first line treatment for narcolepsy, because it is much less likely to be abused
what other stimulants are used for narcolepsy
armodafinil - inhibits DA reuptake and elevates hypothalamic histamine
dextroamphetamine, methylphenidate
while the exact cause of narcolepsy is unknown, it may be caused by///
reduced amounts of the hypothalamic protein hypocretin/orexin - which may be caused by an autoimmune disorder triggered by the H1N1 virus
stimulant/amphetamine adverse reactions
insomnia, addiction potential, dopaine reward pathway overstimulation causing amphetamine psychosis
characteristics to be diagnosed with ADHD
symptoms begin before the age of 7, persist for longer than 6 months and in at least two settings
phtermine is a stimulant drug that promotes NE and DA release, it has been used to treat…. because it stimulates the anorectic centre
obesity - by supressing appetite in the hypothalamus
what are the two types of neurons which originate in the arcuate nucleus and converge on the paraventicular nucleus involved in appetite
orexigenic neurons stimulate appetite -
anoretic neurons inhibit appetite
orexigenic neurons are stimulated by ghrelin to induce appetite by releasing
neuropeptide y and agouti related peptide
orexigenic neurons are inhbited by
leptin,, insulin, and peptide yy (these will stop feelings of hunger)
anorectic neurons stop appetite, and they are stimulated by leptin and insulin to release
alpha melanocyte stimulating hormone
factors that stimulate appetite
neuropeptide Y, agouti related peptide, orexin, ghrelin (ghrelin stimulates orexigenic neurons to release NPyY, AgRP) as well as THC and endocannabinoids
factors that inhibit appetite
leptin, GLP-1, cholecytokinin, peptide YY
serotonon stimulates anorectic neurons and inhibits oxigenic neurons
topiramate is an antiepileptic drug that increases GABA while inhibiting glutamate, but due to its anorectic effect it can also treat
obesity
naltrexone and bupropion are anti-obesity agents which work by
altering the DA reward pathways to lesson the feel good feeling from eating and stimulate anorectic neurons
orlistat is an OTC anti obesity drug that does what
inhibits pancreatic and intestinal lipases to prevent the absorption of dietary fats but also vitamins
causes bad GI symptoms like really foul smelling feces
liraglutide is an anti-obesity agent which is indicated for those with conditions like diabetes, hypertension, and dyslipidemia. it works by
GLP-1 agonist acting in the appetite center by stimulating insulin release and reducing glucagon
what are the three endogenous opiod peptide producing genes
pro-opiomelanocortin (produces beta-endorphins, adrenocorticotropic hormone, and melanocyte stimulating hormone
pro-enkephalin - (enkephalins)
pro-dynoprhin (dynorphins)
describe the pain sensory system
painful stimuli enter from the dorsal horn of the spinal cord and release and are carried by afferent neurons to the thalamus, limbic system, and somatosensory cortex to release glutamate and substance-p
describe the pain inhibitory system
originating in the midbraun and raphe magnus, descending tracts project into the dorsal hor to inhibit the activity of the ascending pathways using NE and serotonin
while endogenois opiod peptides are well known for their ability to modulate pain transmission, they also modulate …
GI function, increasing random contractions of circular muscles causing constipation
endogenous opiod peptide receptors are coupled to G proteins which, when activated, decrease cAMP to create an efflux of potassium, decreased Ca influx - ultimately DECREASING THE RELEASE OF NTs
What are the three types
Mu receptors - stimulated by beta-endorphins - analgesia, euphoria, and the resp depression
Kappa - dynorphin stimulation - analgesia with LESS euphoria
Δ - enkephalins - analgesia
Butorphanol is an opiod analgesic which is preferentially affecting kappa receptors giving it this major benefit
it does not cause euphoria so its less addictive
the two natural opiod agonists, derived from the opium poppy, are Morphine and Codeine. They preferentially affect this opioid receptor
mu receptor, morphine is much more potent
codeine is converted to morphine by CYP 2D6
meperidine, methadone, and tramadol are all synthetic opioids which affect this receptor - compare and contrast
they all affect the mu receptor, but:
- meperidine causes less psychosis but may cause respiratory impression
- methadone has a very long half life so ut can be used for addiction and chronic pain
- tramadol is ALSO an SNRI so it helps inhibit pain transmission
what characteristics of fentanyl make it so dangerous
very potent, lipophillic, and fast acting with a short duration
list the two opiod antagonists and the main difference between them
naloxone and naltrexone. both block the actios of all EOP receptors, but naltrexone has a much longer half-life and an active metabolite with a long half life
opiods are metabolized by
hepatic glucuronidation
this major class of non-narcotic analgesics work by inhibiting COX enzymes to stop the production of prostaglandins
NSAIDS
how do prostaglandins facilitate pain
- sensitize nociceptors to chemical pain mediators (bradykinin, cytokines, substance P)
- increase blood flow to injured area which increases leukocyte infiltration causing swelling and inflammation
- peripheral inflammation inducing COX-2 causing fevers and inflammation
non-selective COX inhibitng NSAIDS such as _____ work byinhibiting both COx I and II
Asprin and ibuprofen
- inhibit pain transmission and reduce elevated body temps without lowering them below normal
COX I inhibition caused by ASA and ibuprofen leads to these adverse effects
GI irritation and ulcers due to decreases in mucus and increases in acid
decreased blood coagulation
decreased renal blood flow and interstitial nephritis
how is ASA overdose possible
at high doses the hepatic enzymes are overwhelmed, greatly increasing the half life of ASA
what are two examples of selective COX-II inhibitors and their advantages
celecoxib - reduces inflammatory mediators WITHOUT GI irritation or platelet aggregation interference
acetaminophen - analgesia and antipyretix actions but NO ANTI INFLAMMATORY actions or anti platelet actions, or gi side effects
neuropathic pain is
a class of diseases causing pain, hyperalgesia (increased response to painful stimuli, allodynia, parasthesias, and dysesthesias) due to afferent neurons hyperactively discharging over time altering them to increase sodium channels
methods of treating neuropathic pain include
sodium channel blockers like carbamazepine and lamotrigine
calcium channel blockers like pregabalin and gabapentin (decrease glutamate release)
5Ht and NE reuptake inhibitors- tricyclic antidepressants like nortriptyline and amitriptyline
general reuptake inhibitors like duloxetine and venlafaxine
trigeminal neuralgia
shooting neuropathic pain in the face in response to non-painful stimuli. can be caused by multiple sclerosis (demyelination) or a pulsating vascular loop
treatment for trigeminal neuralgia
sodium channel blocking AEDS (lamatrigine, carbamazepine, phenytoin)
fibromyalgia
chronic, diffuse pain and allodynia caused by increased pain sensitivity of the brain to pain signals and a reduced pain threshold (central pain sensitization caused by altered neurotransmitter levels and increased sensitivity of nociceptors
treatment for fibromyalgia
AED like pregabalin (Calcium blockers that decrease glutamate)
tricyclic antidepressant amitriptyline
gout
inflammatory joint disease - uric acid crystals build up in joints, attracting leukocytes and causing inflammation and joint damage
acute treatment for gout
reduce pain and inflammation:
- NSAID and corticosteroids (prednisone) to decrease prostanoid synthesis
- colchicine - decreases inflammation and phagocytosis by leukocyte migration by disaggregating microtubules
long term treatment of gout
decrease uric acid
- allopurinol - block xanthine oxidase (inhibit the synthesis of a uric acid precursor)
- probenecid - increases urate kidney excretion
two main pharmacological actions of caffeine
adenosine receptor blocker, phosphodiesterase inhibitor
mechanism of action for maarijuana as a depressant
THC and CBD receptors are G protein linked and when they are activated, they decrease cAMP production, leading to reduced activity of NE DA and glutamate
anandamide and 2-AG are examples of two endogenous…
cannabinoids
speed balls (heorin and coke) and R&Ts (ritalin and talwin) are examples of
upper and downer combo - potentiates the feelings of euphoria
ergotamines, mescaline (from the peyite cactus) and atropine and scopalamine are examples of
hallucinogens
how do hallucinogens work
- increase neural activity in NE, DA and 5HT
- reduce ACh pathways
opiod dependency treated with
methadone (long acting oral dose pain reliver)
naloxone or naltrexone (opiod antagonist for overdoses)
nicotine dependency treated with
Nicotine replacement therapy
antidepressant and partial nicotine agonist VARENICLINE
antidepressent buproprion
ethanol works on the receptors of these three NTs
gaba, glutamate (NMDA) and 5HT
supresses neuronal excitability
this brain area is more sensitive to the effects of ethanol
the limbic system
disulfiram is a drug designed to treat alcoholism by
inhibiting the enzyme ALDH, letting acetaldehyde build up causing unpleasant side effects
Acamprosate is a drug used to reduce alcohol cravings by
decreasing the action of Glutamate in the CNS (glutamate antagonist)
Naltrexone and naloxone are opiod antagonists used in opioid overdose, but can also be used to treat alcoholism by
decreasing the dopamine reward pathway
another alcohol, methanol is metabolized to harmful metabolites like formaldehyde and formic acid. To treat methanol ingestion you…
give a person ethanol so the enzyme which produces the formaldehyde and formic acid is overwhelmed
bicarbonate to reduce acidosis
fomepizole - ADH inhibitor to
ethylene glycol is an alcohol that if ingested will be metabolized by ADH to toxic aldehydes and oxalic acid, where oxalate crystals may develop in the renal tubules. to treat this …
wash out with ethanol
use fomepizole to inhibit ADH
add fluids and calcium
multiple sclerosis pathology
demyelination by immune system causing sensory, motor, and cognitive issues
how does multiple sclerosis pathology begin
somehow, a T cell gets activated by myelin - beginning a TYPE IV hypersensitivity reaction (cell mediated) where it releases cytokines (IL-1, IL6, TNF-alpha, INF-gamma) to make the vessels of the BBB leaky so B cells can be recruited. they produce antibodies, and macrophages are also recruited and they attack the myelin causing plaques (sclera) which can be observed on an MRI scan.
what are the four types of MS
- Relapsing remitting - clearly defined attacks separated by periods of remission during which the disease does not worsen/progressive
- Primary progressive - functioning worsens and disability accumulates as soon as symptoms appear without periods of remission or relapse
- progressive relapsing - rare form where steady damage to nerves begins when symptoms first appear, continues to cause progressive worsening even though symptoms go into periods of remission
- secondary progressive - initially follows the pattern of clearly defined attacks separated by periods of remission, but changes to progressively worsening
what is charcot’s neurologic triad
triad of symptoms of MS:
1. nystagmus (shaky eyes)
2. Intention tremor (tremor during intentional, directed movement)
3. unclear speech
what is Lhermitte’s sign
an electrical sensation that runs down the back and into the limbs when you tilt your head down
if MS plaques occur in the ANS, the symptoms might be
bowel and bladder symptoms, sexual dysfunction
what is Uhthoff’s phenomenon
the worsening of symptoms of MS in the heat (because body temperature can slow or block impulse conduction in demyelinated nerves)
the goal for Acute treatment of MS is to stop the inflammation. this is done by
methylprednisolone - immunosuppressive steroid
Plasma Exchange Therapy - discard antibodies replace with albumin and saline
Disease modifying therapies for MS aims to decrease the risk of relapses and slow disability progression. The two main drug classes used for this are
immunomodulators and monoclonal antibody therapy
list the qualities of three immunomodulators (interferon beta, fingolimod, glatiramer acetate) used to treat MS
- interferon-Beta: first line treatment, reduces antigen presentation and T-cell proliferation
- glatiramer acetate: decoy for immune cells (mixture of random sized peptides which contain the amino acids found in myelin basic protein)
- Fingolimod - first oral drug for MS, prevents lymphocytes from entering the CNS in relapses
compare and contrast the following monoclonal antibody therapies used to treat MS:
- Natalizumab
- Alemtuzumab
- Ocrelizumab
- Daclizumab
- natalizumab prevents binding to and crossing the BBB
- Alemtuzumab destroys tagged lymphocytes
- ocrelizumab is the first for primary progressive MS, it kills B cells and has immunosuppressive effects \
- daclizumab - net reduction of T cell response
some drugs can be used to treat the symptoms of MS like difficulty walking and muscle spasms, what are they:
Dalfampridine - used to treat difficulty walking by increasing conduction in the absence of myelin
tizanidine - muscle relaxant, alpha-2 adrenergic agonist
botox - blocks vesicle docking - paralysis
nabiximols - thc
Three A’s (goals) of general anesthesia
Amnesia
Akinesia (stop moving)
analgesia
Nitrous oxide, Isoflurane, Sevoflurane are all anesthetics administered via
inhalation
most anesthetics exert their effects via
enhancing activity of GABAa receptors (increasing inhibition)
compare and contrast the inhalation anesthetics Nitrous oxide and Isoflurane/sevoflurane
both work on GABAa receptors, fluranes are allosteric modulators
N2O gives analgesic effects via endogenous opioids in the BRAIN (not spinal cord)
Fluranes can reduce the dose requirements needed when combined with N2O and O2
these three anesthetics are paralytics (neuromuscular blockers). Compare and contrast
Vecuronium + Rocuronium: non-depolarizing competitive antagonists of nicotinic ACh receptors
- increase safety of anesthesia by reducing the amound needed for muscle relaxation
- Vecuronium has less CV side effects
- Rocuronium faster onset
Succinylcholine - DEPOLARIZING nACh receptor agonist - rapid onset and very short duration, best used for endotracheal intubation
Vecuronium, a neuromuscular blocking paralytic, should not be used in patients with
cardiovascular conditions
compare and contrast the IV anesthetic agents (etomidate and propofol)
both are positive allosteric modulators of GABAa receptors, and become GABAa agonists at high doses
etomidate is good because it has little/no effect on the heart - making it safe for older patients who often have CV conditions, but it causes adrenal supression so it is only used for rapid induction of anesthesia or short procedures like fixing broken bones or tracheal intubation
Large discrepancy in the half life and duration of action of etomidate - gets sequestered into different body compartments
Propofol may act on endocannabinoid system, has rapid onset and recovery time with amnestic effects
Midazolam is an anxiolytic which can also be used for surgery to
be used as a pre-anesthetic to calm a patient down
Dezmedetomidine is an anesthetic which is different because it does not work on the GABA system, but rather exerts its effects on
alpha2-adrenergic receptors (as an agonist, these receptors are inhbitory in nature)
it is good because it is easily and rapidly reversible
in which order might you use these anesthetics:
iso/sevoflurane + N2O
propofol + fentanyl
vecuronium
midazolam
use midazolam first to induce amnesia and calm a patient
then induce anesthesia wth either propofol + fentanyl, or vecuronium
next maintain the anesthesia with iso/sevoflurane with N2O, or propofol with fentanyl while monitoring brain waves and vitals
lidocaine and bupivacaine are ____ anesthetics
local anesthetics
how do lidocaine and bupivacaine work
they block sodium channels in smaller, unmyelinated nerves (Adelta and C fibre axons)
the order of sensory blocking for local anesthetics
temperature, pain, touch, pressure, motor
patients who have CV conditions can use this anesthetic agent for the induction of anesthesia
Etomidate because it has less vasodilation and myocardial depression
what is Amyotrophic lateral sclerosis (ALS)
progressive loss of motor neurons that control the voluntary muscles (neurons of the pyramidal system)
primary lateral sclerosis involves
the death of only upper motor neurons
progressive muscular atrophy (form of ALS) involves only
the death of lower neurons
the hallmark of ALS pathology is
the presence of protein aggregates of TDP-43 and SOD1
SOD1 protein is an anti-oxidant, so the aggregates of these result in a los off anti-oxidant capabilities
is glutamate activity increased or decreased in ALS
increased, the excitatory amino acid transporter EAAT2 has been decreased so Glutamate sticks around longer making the neurons hyperexcitable
neurons are hyperexcitable due to increased glutamate activity in ALS. Which drug combats this
Riluzole - glutamate reuptake and potentiation of GABA
protein aggregates of SOD1 lead to decreases in anti-oxidant capacity in those with ALS, which drug combats this
edaravone - free radical scavenger - first in class ALS treatment - must be administered via IV daily so can affect quality of life
the hallmark of ALS is protein aggregation. what drug combats this
AMXOO35 - fixed dose combo of sodium phenylbutyrate and taurursodiol - chemical chaperone to prevent protein aggregation and improvements in mitochondrial energy production to inhibit cell death pathways in the mitochondria and ER
what is Huntington’s disease
genetic disease of the basal ganglia due to a triple repeat of the DNA sequence (CAG) resulting in mutant proteins (mHtt) which damage brain cells
tetrabenazine and deutetrabenazine are used to treat huntingtons disease by
reversible depletion of DA, 5HT, NE, and HA from nerve terminals
deutrabenazine is an isomer of tetrabenazine which uses deuteriums instead of hydrogens to reduce drug metabolism rate
tetrabenazine and deutetrabenazine are used to treat huntingtons disease but should not be used in patients who have
depression - would reduce dopamine and serotonin levels
Laquinimod is a drug initially developed to treat MS but is used to treat huntington’s disease because it
reduces caudate atrophy and brain atrophy in general
memantine is a partial antagonist of NMDAR glutamate receptors but it is used to treat HD why
decreases the progression of cognitive symptoms by reducing glutamate hyperexcitation leading to cell death
risperidone is an atypical neuroleptic which is also used to treat HD why
dopamine block to reduce motor symptoms
while there is a lot of overlap in
