Exam 4 Concepts Flashcards
dumping syndrome
pyloric sphincter does not work
surface mucous cell
secretes mucous
mucous neck cell
secretes mucus
parietal cell
secrets hydrochloric acid and intrinsic factor
chief cell
secretes pepsinogen and gastric lipase
G cell
secretes the hormone gastrin
where does gastric acid come from?
secreted by parietal cells at basal rate and in response to stimuli
via proton pump (H+-K+ pump aka gastric pump)
how does proton pump work?
moves H+ ion out of parietal cell and into stomach lumen and K+ ion back into cell AGAINST concentration gradients (splits ATP)
Cl- also moves into stomach to form HCL with H+
what stimulates acid secretion beyond basal secretion
gastrin
acetylcholine
histamine
H2 receptor
G Protein-Coupled receptor (GPCR)
- histamine binds, activating alpha subunit of G protein
- subunit dissociates and binds to AC
- AC converts ATP to cAMP
- protein kinase A activated and phosphorylates proteins that transport H/K pump to plasma membrane
LES normal tone
LES is normally a high pressure zone with pressure exceeding intragastric pressure
acid disorders result from…
imbalance of aggressive/damaging factors and mucosal defense factors
mucosal resistance
mucus layer + HCO3-
gastric empyting
moves substances along and sweeps away H+ ions that might leak through
epidermal growth factor
ensures rapid turnover of epithelial cells, enhancing repair of any damage to the epithelium - wounds heal quickly
maintaining the integrity of the gastric mucosal barrier
- HCO3-
- pH of mucosa = 7; pH of lumen = 2
- mucous cells = physical barrier; release mucus
- mucin proteins to maintain barrier fxn
mucins
large, heavily glycosylated proteins which gives them a high degree of water-holding capacity and resistance to proteolysis
sticky, hold together - form gel-like barrier
GERD
gastroesophageal reflux disease
symptomatic condition or histologic change associated w/ retrograde movement of gastric contents to esophagus
PUD
peptic ulcer disease
gastritis, erosions, ulcers of GI tract that require gastric acid for formation
duodenal ulcers more common than stomach ulcers
most common cause of GERD
incompetent LES - allows acid reflux
LES
lower esophageal sphincter
high-pressure zone of thickened muscle between esophagus and stomach. works in concert w/ diaphragm to prevent reflux
normally 15-30 mmHg above intragastric pressures
other causes of GERD
anything that alters normal fxn and/or tone of LES OR increases abdominal pressure
certain foods/meds smoking obesity hiatal hernia pregnancy sleeping positions
hiatal hernia
stomach bulges up into chest through opening where esophagus passes through diaphragm
sliding hiatal hernia
stomach and section of esophagus that joins stomach slides up chest through hiatus
more common
paraesophageal hernia
stomach squeezed through hiatus and next to esophagus - stomach can become incarcerated and blood supply cut off
more dangerous
peppermint
relaxes LS (carminative)
calcium channel blockers
relaxes muscles (esophageal sphincter)
cigarette smoke
direct esophageal irritant
typical GERD symptoms
heartburn in sternum water brash (hypersalivation) belching regurgitation w/w/out nausea worse when supine
complication symptoms of GERD
continual pain dysphagia odynophagia (pain) vomiting acid in sleep bleeding unexplained weight loss choking
atypical (extra-esophageal) symptoms
non-allergic asthma chronic cough hoarseness laryngitis chest pain dental erosions
Barrett’s esophagus
metaplasia due to chronic exposure to gastric acids
stratified squamous replaced by columnar w/ goblet cells - more likely to develop adenocarcinoma
pts. need monitoring
GERD complications
delayed gastric emptying
increased frequency of transient LES relaxations
increased acidity
loss of secondary peristalsis following transient LES relaxations
decreased LES tone
common causes of PUD
helicobacter pylori infection
NSAIDS
smoking increases risk
characteristics of H.pylori
G-
slow-growing
flagella to move below mucosal surface
how H.pylori infection can lead to PUD
well-adapted to gastric environment - lives w/in or beneath gastric mucosal layer
disrupts mucosal layer, neutralizes pH (mucin degels), releases enzymes and toxins, adheres to gastric epithelium
promotes inflammatory rxn and inhibits apoptosis of host cell
mucosal disruption leads to tissue injury, erosion, ulcer
H.pylori flagella in mucosal injury
bacterial mobility and chemotaxis to colonize under mucosa
H.pylori urease in mucosal injury
neutralize gastric acid
gastric mucosal injury via ammonia
H.pylori lipopolysaccharides in mucosal injury
G-
adhere to host cells
inflammation
H.Pylori outer proteins in mucosal injury
adhere to host cells
H.Pylori effectors in mucosal injury
actin remodeling
Il-8: pro-inflammatory, host cell growth, inhibits apoptosis
H.pylori secretory enzymes in mucosal injury
mucinase, protease, lipase: gastric mucosal injury
H.pylori type IV secretion system in mucosal injury
pilli-like structure for injection of effectors
diagnosing H.pylori infection
biospy via endoscopy = gold standard
H.pylori breath test - non-invasive and reliable
H.pylori serum antibodies sometimes measured, but not recommended for diagnostic purposes
H.pylori breath test
- H.pylori releases urease which breaks urea down into CO2 and ammonium
- carbon-12 more abundant than carbon-13
- pre/post test with liquid urea from carbon-13
- 13C-urea broken into 13CO2 and NH4 if H.pylori is present
- 13CO2 absorbed into stomach, bloodstream, and exhaled out lungs
pre and post ratios of 13CO2 and 12CO2 measured - increased ratio means H.pylori
NSAIDs can cause PUD
long-term/high-dose therapy
direct topical injury to gastric mucosa
increased neutrophil adherence to vascular endothelium –> neutrophil-derived ROS and proteases –> damage to mucosal layer
inhibit beneficial prostaglandins
prostaglandin inhibition in PUD
decreased submucosal blood flow - ischemia
decreased mucosal proliferation
decreased production of mucus and bicarb (allows erosion in presence of HCl)
increased secretion of gastric acid and pepsin
risk factors for NSAID-induced PUD
>65 previous Hx of PUD combined NSAIDS combo with corticosteroids smoking heavy alcohol consumption
stress uulcer prophylaxis
71% of pts on gen med units receive acid-suppressing therapy without an appropriate indication
stress ulcer prophylaxis recommended in ICU pts. with following symptoms:
coagulopathy prolonged ventilation GI ulcer/bleeding in past yr sepsis >1 week in ICU occult GI bleeding > 6 days steroid therapy > 250mg daily
PUD symptoms
general, mild epigastric pain nausea food aggravates gastric pain food relieves duodenal pain may be asymptomatic anemia w/ bleeding
PUD complications
bleeding: black/tarry stools or hematemesis (coffee ground)
perforation
obstruction
non-pharmacologic approaches for GERD and PUD
lifestyle (GERD)
discontinue NSAIDS (PUD)
surgery
GERD lifestyle modifications
elevate head of bed
dietary changes: avoid certain foods, eat small meals, avoid eating w/in 3 hrs of laying down
weight reduction if appropriate
stop smoking/drinking
avoid tight-fitting clothes
discontinue meds that exacerbate
oral regimens to eradicate H.pylori-induced PUD
PPI and 2 antibiotics
1 and #2 cause of ESRD
#1: diabetes #2: hypertension
proper kidney fxn: set body fluid volume and composition
maintain stable volume and composition of body fluids
reabsorb filtered nutrients (glucose, amino acids)
retain blood cells/proteins in bloodstream, and not leak into urine
composition of body fluids balanced by kidney
water sodium potassium calcium phosphorus acid/base
kidney excretion of wastes
creatinine
urea
metabolic end products of drugs and hormones (liver conjugation –> water soluble)
acid (meat consumption)
creatinine
product of muscle metabolism
urea
product of amino acid metabolism
endocrine fxns of kidneys
erythropoietin
Vit. D conversion to active form
Renin
erythropoietin
RBC growth factor
release stimulated by hypoxia
binds with receptors in bone marrow to stimulate production of RBCs
Vitamin D conversion to active form
kidney performs second hydroxylation of vitamin D to form active form of Vit. D necessary for calcium absorption
renin
regulates blood volume and blood pressure via renin-angiotensin-aldosterone system
renal blood flow
kidneys = 1% body mass
receive 20-25% CO
normal glomerular filtration rate
125mL/min
actual rate of urine production = 1.5 L/day
nephron structures
glomerulus PCT loop of Henle DCT collecting tubule
juxtamedullary nephrons
loop of Henle extends through cortex into medulla
low blood flow - vulnerable to ischemia
glomerulus
site of filtration from blood
formed by glomerular capillary tuft, podocytes of Bowman’s capsule, basement membrane
basement membrane and proteins in slit pores of podocytes
prevent passage of cell snad large proteins
mesangial cells
in basement membrane of glomerulus
structural support for glomerular capillaries, secretion of matrix proteins, phagocytosis, regulate GFR
by contracting/relaxing, mesangial cells alter available surface area for filtration and affect GFR
mesangium
mesangial cells + mesangial matix
mesangial cells in diabetic-induced CKD
become fibrotic so they can’t contract and relax anymore
filtration through glomerulus
10% renal blood flow leaves circulation and enters glomerular space via glomerular filtration
fluid = ultrafiltrate of plasma (water, ions, small molecules, a.a, urea, creatinin, drugs, hormones)
blood cells/proteins retained in bloodstream
negative charges in basement membrane and podocytes
repel proteins
key factor in glomerulus ability to prevent plasma proteins leaking into urine
remaining tubular structures process fluid and return 99% water/substances back to circulation
steps in glomerular filtration
- glomerular filtrate leaves vascular space, enters urine at glomerular capillaries
- water, electrolytes, glucose, others substances reabsorbed by renal tubules and return to circulation by peritubular capillaries
- remaining fluid is hypertonic
GFR overview
gold standard method of expressing kidney fxn
how can glomerular capillaries have such a high filtration rate relative to other systemic capillaries?
high glomerular hydrostatic pressure (pushing force for fluid)
glomerular capillaries have high surface area and high permeability. highly fenestrated (50X more permeable than muscle capillaries).
glomerular capillaries, basement membrane, podocytes, allow filtration: movement of water/small solutes but RESTRICT protein movement from blood to Bowman’s space
regulation of GFR
proportional to number of nephrons - declines w/ age
proportional to renal blood flow
mechanisms of kidney injury
acute, often reversible injury (such as nephrotoxic antiboitic drugs) vs. chronic injury
glomerular abnormalities (acute or chronic)
sclerosis of glomerular basement membrane
scarring and deposit of immune complexes (infection, SLE)
loss of basement membrane negative charges that normally repel protein filtration
effacement of podocytes (change in morphology - thin and narrow)
tubular injuries
more common in acute kidney injury
ischemic insult to deep medullary interstitium
increased vulnerability to ROS
hyperfiltration, particularly with protein leakage
causes of glomerular scarring and injury
deposition of immune complexes and antibodies in interstitium due to:
- strep
- viral infections
- systemic lupus erythematosus
- IgA nephropathy
loss of nephrons to diseae =
loss of GFR
DM in ESRD
chronic hyperglycemia leads to hyperfiltration and increased albumin excretion
-hyperfiltration becomes source of injury
hyperglycemia modifies endothelial cell properties and proteins in glomerular basement membrane, altering structure and fxn of filtration barrier
various processes contribute to excessive vascular leakiness in kidneys
ROS damage and inflammation damage endothelium
basement membrane becomes thickened, sclerotic, loses (-) charge
podocytes effaced, lose interlocking characteristic
hypertension in ESRD
arteriosclerosis of small arteries and arterioles
-reduced renal blood flow, glomerular scarring
measurement and estimation of GFR
Modification of Diet in Renal Disease (MDRD)
serum creatinine
normally freely filtered in glomerulus and excreted in urine at constant rate
-dependent on muscle mass and GFR
decease in GFR, decrease creatinine excretion
-serum creatinine increases because it’s not being excreted
urea as marker of renal fxn
end-product of protein metabolism
BUN (blood urea nitrogen) can vary with hydration status and renal fxn
-looked at relative to changes in creatinine (less specific marker)
albuminuria as marker of renal fxn
albumin leaks through when glomerular barrier loses integrity
definition of CKD
abnormalities of kidney fxn for >3 months, with implications for health, including either:
- marker of kidney damage
- decreased GFR
markers of kidney damage
albuminuria urine sediment abnormalities electrolyte/other abnormalities histological evidence of abnormality imaging evidence of abnormality history of kidney transplant
CKD on a continuum
- normal
- increased risk
- damage
- decreased GFR
- kidney failure
- death
concomitant diseased with CKD
16-40X more likely to die of other diseases (esp. CVD) than progress to kidney failure
Stage 1 CKD by eGFR
eGFR > 90
normal or high GFR
(kidney failure if other marker of abnormality)
Stage 2 CKD by eGFR
eGFR 60-89
mildly decreased GFR
(kidney failure if other marker of abnormality)
Stage 3a CKD by eGFR
eGFR 45-59
mildly/moderately decreased GFR
Stage 3b CKD by eGFR
eGFR 30-44
moderately/severely decreased GFR
Stage 4 CKD by eGFR
eGFR 15-29
severely decreased
Stage 1 CDK by albuminuria
ACR (albumin to creatinine ratio)
Stage 2 CDK by albuminuria
ACR 30-300
moderately increased
Stage 3 CDK by albuminuria
ACR > 300
severely increased
major consequences of CKD
hypertension anemia metabolic acidosis bone disorders CVD
hyperphosphatemia and hypocalcemia in CKD
phosphorous and calcium can bind together and form a complex (also bound in bone)
hyperphosphatemia –> hypocalcemia
urinary excretion of phosphorus is impaired, so calcium binds to phosphorus in gut and is excreted, and causes calcification in soft tissues (vascular calcification)
impaired Vit. D activation –> decreased calcium absorption
hypocalcemia and decreased Vit. D activate parathyroid glands which mobilize calcium from bones via parathyroid hormone (PTH)
CKD-MBD
chronic kidney disease - mineral and bone disorder
CVD greatly increases risk of cardiovascular disease
clinical presentation of nephron loss in CKD, stages 1-3
fluid and electrolyte imbalance (hypertension)
anemia (seen in all stages as CKD progresses)
clinical presentation of stages 4/5
severe fluid and electrolyte imbalance with elevated creatinine and BUn
hyperkalemia, hyperphosphatemia, hypocalcemia, metabolic acidosis
hypertension, CHF, PE
hypoalbuminemia
what is the effect of hypoalbuminemia on capillary colloid osmotic pressure?
less albumin in blood causes decreased capillary colloid osmotic pressure. This will cause an increase in edema because fluid is being held in blood vessels, which eventually leaks out.
major causes of death in CKD
MI
stroke
PVD (vessel calcification, hyperlipidemia)
clinical presentations of CKD
blood abnormalities hormone imbalances bone disease neuromuscular abnormalities GI abnormalities skin abnormalities
anemia in CKD results from:
deficiency erythropoietin
decreased RBC lifespan
nutritional deficiencies (iron, b12, folate)
dialysis-related blood loss and hemolysis
FATIGUE
principles of CKD nonpharmacologic management
manage diabetes/hypertension via lifestyle changes
avoid nephrotoxic agents
medical nutrition therapy
- decreased protein intake
- decreased Na, K, phosphate
- Vit. D and Ca supplementation
- Iron/B12 reduce nutritional sources of anemia
renal replacement therapy
- discussion occur during late stage 4 CKD to determine method of RRT and create vascular access
- not a strict numeral cut-off point for RRT
hemodialysis
2/3 pts with end stage renal disease
passes through semipermeable membrane from dialysis fluid
dialysis fluid composition set to correct electrolyte imbalances and remove wastes
heparin used to prevent clotting
patients tired by next appointment because toxins have been building up over the past few days
arteriovenous anastomosis
A-V fistula: artery and vein joined. vein thickens over time due to increased pressure flowing backward
most common vascular access procedure
arteriovenous graft
A-V graft: artificial graft put in between vein and artery
more problems with clotting and infection
peritoneal dialysis
individual’s peritoneal membrane serves as semipermeable membrane
dialysis fluid instilled in abdomen via implanted catheter; drained and replaced after time delay
cycle repeats several times a day
can be done at home or during sleep
renal transplantation
first and most common organ to be transplanted
living or cadaver donors
blood typing/tissue typing done in advance of living donor
check for antibodies in recipient that may react with donor cells (negative crossmatch)
principles of pharmacotherapy for CKD
prevent progression
management of complications
anemia correction
iron supplementation therapy to bind oxygen, maintain adequate iron stores, promote response of erythropoietin
hematopoietic agents: promote RBC production
-requires adequate iron, B12, folate
phosphate binders
MOA: reduce intestinal absorption of dietary phosphate (from proteins) by binding to phosphate in intestinal lumen
two kinds:
- calcium-based: calcium carbonate and calcium acetate
- calcium-free: sevelamer HCl and sevelamer carbonate and lanthanum carbonate
neuropharmacologic medications
alter axonal conduction
alter synaptic transmission
axonal conduction medications
less common
not selective; impulse is same in all neurons
synaptic transmission medications
most common
can be selective; different transmitters and receptors
work by influencing receptor activity on target cells
steps in synaptic transmision
- synthesis of transmitter
- storage of transmitter
- release of transmitter
- action at receptor
- termination of transmission
synthesis of transmitter
from precursor molecules
storage of transmitter
in vesicles
release of transmitter
action potential causes vesicles (via Ca-gated channels) to discharge contents into synaptic cleft
action at receptor
transmitter binds (reversibly) to its receptor on postsynaptic cell to illicit a response
termination of transmission
transmitter dissociates from receptor and is removed by:
a) reuptake into nerve terminal
b) enzymatic degradation
c) diffusion away from gap
reuptake of NT
most common
secondary active transport - sodium down its concentration gradient moves NT against its concentration gradient back into presynaptic terminal
-store or broken down
class of neurotransmitter receptors
ionotropic receptors
metabotropic receptors
ionotropic receptors
NT binding directly opens ion channel and changes postsynaptic membrane potential
rapid signaling
metabotropic receptors
NT binding activates G protein, resulting in 2nd messenger production and/or ion channel opening
slower signaling
characteristics of ionotropic receptors
ligand-binding site for NT
central pore w/ ion selectivity
rapid activation
ability to rapidly change membrane potential to depolarize (EPSP) or hyperpolarize (IPSP)
EPSP
excitatory postsynaptic potential
sodium or calcium movement into cell via ionotropic receptors causes depolarization (membrane closer to or at threshold)
principal NT: gluatamte
IPSP
inhibitory postsynaptic potential
potassium/chloride movement into cell via ionotropic receptors causes hyperpolarization (membrane further from threshold)
principal NT: GABA
characteristics of metabotropic receptors
7 membrane-spanning regions (serpentine regions)
G-protein coupled receptors w/ NT binding site
work thru enzymes that generate 2nd messengers
G proteins can directly couple to ion channels
slower changes in membrane potential (depol. or hypol.)
can produce intracellular changes (ex: altered gene expression) - slow
modes of neurotransmission
fast - ligand-operated
slow - intracellular 2nd messengers
“fast” neurotransmitters
glutamic acid
ACh
GABA
glycine
“slow” neurotransmitters
biogenic amines
peptides
types of neurotransmitters
amino acids
amines
others
amino acid NTs
glutamate (excitatory)
GABA (inhibitory)
mainly ionotropic
direct actions w/ purposeful activity
all brain regions
drugs may have widespread effects
amine NTs
dopamine norepinephrine serotonin ACh (sometimes) others
mainly metabotropic slow, modulatory, widespread activity discrete brain cell clusters axons spread through CNS drugs may act on behavior, sleep, appetite, mood, emotions
glutamate
principal excitatory transmitter - most of the rapid transmission (sensory, motor, vision, hearing, consciousness)
receptors: AMPAr, NMDAr
contributes to learning/memory via NMDAr
converted to glutamine by glial cells after reuptake - sent to presynaptic terminal (or repackaged into vesicles at presynaptic terminal)
GABA
synthesized from glutamate
principal CNS inhibitory NT
GABA receptors
GABAa - ionotropic/ligand-gated
GABAb - metabotropic
both produce IPSPs (inhibitory)
GABAa
GABA binds to receptor chloride channel opens Cl flows in hyperpolarization decreased ability to fire inhibitory
acetylcholine
first NT identified (peripheral nervous system)
NT of:
- all motor neurons
- all autonomic preganglionic neurons (parasymp. and symp)
- parasympathetic postganglionic neurons
- a few sympathetic postganglionic neurons (sweat glands)
acetylcholine synthesis
choline + acetyl COA --(CAT)--> acetylcholine --(AChe)--> choline + acetic acid
CAT
choline acetyltransferase
synthetic enzyme
AChE
acetylcholinesterase
inactivation enzyme
cholinergic neurotransmission
ACh uses enzymatic breakdown for NT termination
ACh binds with its receptors - degraded by acetylcholinesterase
choline returned to presynaptic nerve terminal for re-synthesis
major central cholinergic neurons
basal forebrain
basal ganglia
brainstem pedunculopontine nucleus
basal forebrain
central cholinergic neuron
learning, waking
nucleus basalis of Meynert degenerates in Alzheimer’s
basal ganglia
central cholinergic neuron
striatal interneurons
antagonizes dopamine -> motor control
brainstem pedunculopontine nucleus
central cholinergic neurons
REM sleep initiation
dopamine nuclei
midbrain substantia nigra
midbrain ventral tegmental area
hypothalamus
midbrain substantia nigra
dopamine nucleus
motor control via projection to basal ganglia
midbrain ventral tegmental area
dopamine nucleus
mesolimbic/mesocortical tract –> motivation/activation/pleasure/reward/addiction
hypothalamus
dopamine nucleus
tuberoinfundibular system releases DA to inhibit pituitary prolactin secretion
nucleus acumbens
location of pleasurable/reward effect of dopamine (in forebrain)
norepinephrine nuclei
locus ceruleus
locus ceruleus
main NE nucleus related to behavior - wide projections to all cortical regions, cerebellum, spinal cord
implicated in: arousal/awakening increases attention stress-mediated activation ADHD, PTSD mood and affect pain modulation
serotonin nuclei
raphe nuclei
raphe nuclei
all levels of brainstem - pathways target all cerebral cortex
implicated in:
arousal, awakening, food intake
mood and affect
pain modulation
dopamine, NE, serotonin
metabotropic receptors (except 5HT)
action terminated by reuptake transporters
transmitter release modulated by autoreceptors
excess transmitter metabolized by monoamine oxidase (MAO)
dopamine and NE also metabolized by COMT
autoreceptors
receptors for a particular NT on presynaptic membrane
provide feedback: when too much NT in synapse, activation of autoreceptors decreases release of more NT
depression risk factors
genetics stress emotional trauma comorbidities post-partum SAD
Major Depressive Disorder
MDD
a least 5 of the following symptoms during same 2-week period: depressed/irritable* diminished interest* weight loss/appetite disturbance sleep disturbance psychomotor agitation/retardation fatigue worthlessness trouble concentrating thoughts of death/suicide
*symptoms must be one of these
anxiety risk factors
genetics emotional trauma injuries, illness loss/grief stimulants certain illnesses (hyperthyroidism) infection
anxiety disorders definition
caused by interaction of biopsychosocial factors interacting with situations, stress, trauma
symptoms vary
3 groups
3 groups of anxiety disorders
anxiety
obsessive-compulsive
trauma/stressor-related
anxiety disorders
panic
generalized
social
agoraphobia
obsessive-compulsive/related disorders
OCD
body dysmorphia
hoarding
trauma/stressor-related disorders
PTSD
acute stress
adjustment disorder
regions of brain associated with depression
amygdala
prefrontal cortex
hippocampus
thalamus
amygdala
limbic system
controls autonomic responses of fear, arousal, stress, formation of memories of emotional events
activated with emotionally-charged memory recall
changes in volume/activity observed in depression
increased activity observed to continue even when depression is resolved/remission
prefrontal cortex
executive fxn of brain: discrimination btwn conflicting thoughts, planning complex cognitive behaviors, working toward a goal
inhibits activity of amygdala to allow focus on tasks
decreased PFC activity in depressed people (less suppression of amygdala)
hippocampus
spatial orientation and long-term memory
depressed patients may exhibit memory loss or memory recall difficulties
-perhaps due to decrease in physical volume as well as fxn
thalamus
receives sensory info and relays to cerebral cortex
links sensory input to pleasant/unpleasant feelings
arousal, wakefulness, alertness
increased size in part involved in emotion (increased # of neurons too)
amine hypothesis of depression
increased synaptic amines produce secondary, downstream neuroplastic changes
involve transcriptional/translational changes in receptors and how they respond to 5HT and NE
b/c mood-elevating properties require weeks of treatment, despite immediate increases in amine NT transmission
neurotrophic hypothesis of depression
increased stress hormones cause a decrease in brain-derived neurotrophic factor (BDNF) which causes hippocampal cell atrophy and reduce NT activity in hippocampus
antidepressants:
- improve BDNF activity (promotes growth/survival of neurons in hippocampus)
- promote growth factors in hippocampus (neurogenesis)
other theories of depression
excess serum glucocorticoids cause hippocampus atrophy (more vulnerable b/c of many glucocorticoid receptors)
glutamate’s role (ketamine is a glutamate receptor antagonist)
disruptions in normal gut microbiota
SAD
nonpharmacologic evidence-based approaches to depression
counseling electroconvulsive therapy cognitive behavioral therapy transcranial magnetic brain stimulation vagal nerve stimulation deep brain stimulation phototherapy exercise
cognitive behavioral therapy in depression
- identify the thoughts and images that precede distressing emotions
- distance from beliefs that are embedded into these thoughts and images
- rationally question beliefs
- learn new behaviors and coping skills
general clinical considerations for antidepressants
therapeutic lag
suicide risk
mania risk
adverse effects worst in first 1-2 wks
serotonin syndrome
overstimulation of 5HT(IA) and possible 5HT(2) receptors
risk factors:
SSRI overdose
drug-drug interactions
symptoms: altered mental status autonomic instability neuromuscular dysfxn fever/hyperthermia
SSRI MOA
inhibit reuptake of serotonin to increase concentration in synapse
SNRI MOA
inhibit reuptake of serotonin and NE to increase concentrations in synapse
MAO inhibitors
older class of antidepressants
2nd/3rd choice usually
as effective as TCAs/SSRIs, but more dangerous
hypertensive crisis risk w/ tyramine-rich diet
rigid diet required
forms of MAOIs
MAO-A inactivates NE and 5HT
MAO-B inactivates DA
MAO-A metabolizes dietary tyramine in liver to inactive metabolites
all are nonspecific and will inhibit both types of MAO in brain
MAOIs in brain
inhibit intraneuronal MAO-A to increase NE and 5HT available for release
increased transmission of NE/5HT
tyramine and MAOIs
MAOIs increase NE in synapse
dietary tyramine not metabolized in gut - enters circulation
tyramine displaces NE into synapse - hypertensive crisis
MOA of benzodiazepines
bind to site on GABA(a) receptor and potentiates GABA actions (no effect if GABA is not present)
at high doses barbiturates mimic GABA and are not limited by amount of GABA present
excitable cells
ROM -70mV
when neuron depolarizes to threshold voltage, fast sodium channels open and neuron has an action potential
steps of neuron firing
- graded depolarization brings trigger zone of axon hillock to threshold
- voltage-gated Na channels open –> rapid depolarization
- voltage-gated Na channels inactivated and voltage-gated K channels open –> repolarization
- slow inactivation of K gates –> hyperpolarization
- ion redistribution by Na/K pump restores RMP
what depolarizes a cell to threshold?
chemical transmission (excitatory or inhibitory)
in healthy brain, balance between both so neurons don’t synchronously “fire” inappropriately
summation
spatial
temporal
EPSPs and IPSP can cancel each other out
good NT targets for seizures
glutamate
GABA
good ion channel targets for seizures
sodium
calcium
chloride
potassium
brain electrical activity while awake
widely distributed activity
brain electrical activity while asleep
more synchronized - larger numbers firing in fewer places
EEG
captures brain activity
common causes of a single seizure
head trauma stroke brain infection tumors eclampsia hypoglycemia drug/alcohol acute effect/withdrawal childhood fever
age-relatedi ncidence of epilepsy
u-shaped relationship
more common in older adults because of neurodegenerative diseases
GABA may have paradoxical (excitatory not inhibitory) effect on infants
% of patients w/ uncontrolled seizures
1/3
b/c no available treatment works
risk factors for developing epilepsy
traumatic brain injury brain tumor stroke CNS infections dementia hypoxia Down Syndrome Cerebral Palsy autism migraine w/ aura (esp. in children) family Hx febrile seizures past expected time frame seizure in first mo. of life recreational drugs
seizure
single occurrence of S/Sx due to abnormal excessive or synchronous neuronal activity in brain
transient
paroxysmal
group of neurons abnormally hyperactive and hypersynchronous form an epileptogenic focus
disturbance of motor control, sensation, behavior, consciousness, autonomic fxn
epileptogenic focus
area of brain from which seizure emanates
fxns autonomously, causing excessive paroxysmal electrical discharges
prodrome
difficult to describe feeling that a seizure may occur - minutes to hours before
anecdotal evidence of “seizure alert dogs”
aura
particular sensory. autonomic or psychic symptom at the beginning of a seizure that is characteristic of seizures
ictal phase
period of time from first symptom (including aura) to end of seizure activity
epilepsy syndromes
clustering of findings of seizures with other clinical phenomena define specific epilepsies
incidence may be unique to a given age group
in some cases a specific gene mutation is the cause
epilepsy
any of the following:
- 2 unprovoked/reflex seizures more than 24 hrs apart
- 1 unprovoked/reflex seizure and probability of further seizures at least 60% after two unprovoked seizures, occurring over next 10 years
- diagnosis of epilepsy syndrome
resolution of epilepsy
person with age-dependent epilepsy syndrome but are past the applicable age or have been seizure-free for 10 years, with no seizure medicines for last 5 years
broad types of seizures
focal and generalized
focal seizures
also called partial
activity begins in one limited area of brain
simple partial seizures
awareness, consciousness, memory preserved
may have focal motor, sensory, autonomic or psychic signs
complex partial seizures
any impairment of awareness or consciousness
may display automatisms: repeating same word, picking at fabric, smacking lips, freezing completely (may have aura; common site is temporal lobe)
second generalization
starts in one focal area, then spreads and becomes generalized
generalized seizures
more severe
synchronous electrical activity throughout brain
absence seizures
petit mal
stare w/ unresponsiveness, rapid recovery
mouth may move, eyes may blink. very brief
more common in children. can be mistaken for daydreaming.
tonic/clonic seizures
grand mal
long lasting, unmistakable motor signs, may bite tongue, become incontinent, slow postictal recovery.
loss of consciousness
tonic phase
stiffening of all muscles
person will cry out, groan, shriek as air is forced past vocal cords.
loses consciousness and falls down
long post-ictal phase of drowsiness, confusion, amnesia
clonic phase
jerking phase
extremities jerk rhythmically and rapidly
atonic seizure
drop seizure
sudden loss of muscle tone. person may drop to ground, drop what they are holding, etc.
myoclonic seizure
brief muscle jerks
status epilepticus
repeated seizures w/o pause. medical emergency
clinical manifestations of seizures
changes in motor control, sensation, behavior, consciousness, autonomic fxn
in focal seizures: may provide clue to localization of epileptigenic focus
in generalized seizures: progression of signs/history can give hints regarding location
careful history needed (pre- and post-ictal characteristics)
common comorbidities of seizures
psychiatric
cognitive
social
frontal lobe seizure symptoms
disruptive behavior
running, screaming, fear, anger, aggression, swearing
temporal lobe seizure symptoms
changes in sense of smell, odd odors, smell that isn’t there
OR
block speech, produce typical automatic movements, repetition
OR
alter consciousness/mood
OR
illusions of sounds
occipital lobe seizure symptoms
visual distortions/images of things not there
seizure triggers
vary from person to person
missed/skipped AED dose sleep deprivation fever, illness flashing lights/bright patterns alcohol/drug use/withdrawal stress menstrual cycle hypoglycemia poor dietary intake specific foods, excess caffeine medicatons that lower threshold
catamenail epilepsy
increase in seizures during specific times of the menstrual cycle
organ dysfxn in seizures
neurons organized in circuits with synaptic links btwn thalamus and cortex
w/in cortex, wave of excitation often followed by inhibition, due to inhibitory neurons using GABA
if sufficient neurons fire together/are inhibited/fire again, synchronized depolarization/hyperpolarization can be detected on EEG as large waves
focal seizure may only show up on a few leads
generalized seizure has more widespread activity
worse case scenario: severe, treatment-refractory, status epilepticus and brain death
general mechanisms of seizures and epilepsy
disruption in balance between neuronal excitation and inhibition
too much excitation or
too little inhibition
sources of neuronal excitation
brain: abrupt source of sensory input
cell: opening channels permeable to Na and Ca
- activation of receptors for glutamate
sources of neuronal inhibition
brain: sleep
cell: opening K or Cl channels
- increased GABA or increased activity of GABA receptors
nonpharmacologic epilepsy treatments
ketogenic diet
vagal nerve stimulation
surgery
therapeutic goals for controlling seizures
early control to allow maintenance of as normal a life as possible
decrease frequency and severity
prevent recurrence
effects of antiepileptic drugs
raise seizure threshold by stabilizing neuronal membranes and suppressing discharge of neurons
suppress propagation of seizure activity by reducing nerve conduction and synaptic transmission
mechanisms of action for antiepileptic drugs
suppress sodium influx
suppress calcium influx
glutamate antagonism
GABA potentiation
seizure treatment algorithm
- start with one AED
- trial alternative agent (cross-taper)
- consider AED combo treatment
drug evaluation for AEDs
trial period
dosage adjustment
seizure frequency chart
plasma drug level monitoring for AEDs
monitors adherence
determines cause of lost seizure control
identifies toxicity causes
adjusting initial doses increass potential for rapid seizure control
most important for major convulsive seizures
patient nonadherence in seizures
50% of treatment failures
promote adherence:
- education about chronicity of epilepsy
- monitor plasma levels
- seizure frequency chart
taper 6 wks to several months
suicide risk with AEDs
FDA blanket warning, esp. topiramate and lamotrigine
carbamazepine and valproic acid may be protective
not assoc. w/ AEDs
more due to illness
suicide/attempts very rare b/c of AEDs
screen all patients for comorbid depression/anxiety
managing status epilepticus
maintain ventilation
correct hypoglycemia
terminate seizures w/ drugs
initiate/start long-term rugs
