4.05.2012
reflection upon exiting medical school
3.27.2012
prohibition and cirrhosis
a comment was made in today's pharmacology lecture-
"US alcohol prohibition reduced rates of liver cirrhosis, and therefore was good for public health in this particular instance."
i think because none of use had ever looked into this question combined with the fact that it seemed so intuitive, we all took it as fact. however i was interested in seeing whether any data exist to support this claim.
national board of economic research published a paper, Alcohol Prohibition and Cirrhosis, by Dills and Miron, in 2003. The paper examined death rates in the context of state and federal prohibitions. All the cirrhosis death rates declined during the prohibition period by 10-20%, they caution concluding this solely to prohibition for the following reasons:
-there have been substantial fluctuations in cirrhosis death rates comparable to the ones seen during prohibition, outside of periods of prohibition
-cirrhosis did not increase to pre-prohibition levels upon repeal
-cirrhosis levels had declined by the time prohibition began, allow little time for this effect
you decide!
3.05.2012
random pharmacology notes
clinical pharmacology notes
takes 3 half lives of elimination to achieve steady state, so drugs w/long half lives o elimination (amiodarone - 40 days) can fool one into changing them before they've reached steady state. don't make any changes to meds unless they have been in patient for greater than 3 half lives.
aminoglycosides and fluoroquinolones are concentration dependent for bacterial infections
penicillins are time dependent
thus don't underdose fluoroquinolones, don't short course penicillins
quinidine is the most potent inhibitor of CYP2D6 in man
clinical clue: nail through the tennis shoe- think s. aureus or p. aeruginosa because these bacteria grow great in sneakers.
fluoroquinolone with Ca2+ (as in milk or iron fortified OJ) going to form Ca fluoroquinolone precipitates in the gut and less antibiotic will be available. this is bad because fluoroquinolones are concentration dependent anti-bacterial agents
interesting findings surrounding acetaminophen and EtOH. Chronic EtOH induces CYP2E1 for which acetaminophen is a substrate. the acetaminophen is metabolized to a hepatotoxic byproduct associated w/liver failure, thus the total recommended daily dosage for acetaminophen for someone who has at least 2 drinks a day is 2gms! interestingly, in binge drinking college kids - EtOH acutely inhibits CYP2E1, thus they are not bound by the same restriction of 2gm/day of acetaminophen-
2.20.2012
clinical pain management notes/ renal notes
random clinical notes from pain management and renal service
Epidural steroid injection
methylprednisolone or triamcinolone - less post injection flare
dilute w/local anesthetic for less atrohpy/rupture
3 causes of lumbar stenosis
1. ligamentum flavum hypertrophy
2. disc bulge
3. facet hypertrohpy/osteophyte
chief complaint: i have back pain.
clinical question: should you image?
in light of data indicating false positive findings on normals, one should image only in cases of:
history of trauma
unexplained weight loss
fever
immunosuppression
h/o neoplasm
steroid use
age >70
intravenous drug use
definite change in neurological status
chronic pain -76.2 million people in US
20% of outpatient office visits
12% of prescriptions
untreated pain estimated economic impact ~$100 billion/year
pain categories by etiology
nociceptive (somatic, visceral) - this pain is adaptive (keep you out of trouble)
musculoskeletal/inflammatory/mechanical
neuropathic - (this pain no longer helpful, lingers, remains past point of being informative)
sympathetically mediated
peripheral (post herpetic neuralgia, neuromas)
central (post stroke, phantom limb)
nociceptive afferents come in two categories
peptidergic - calcitonin gene related peptide (CGRP), somatostatin, trkA, trpV1
non-petidergic -purinergic ligand gated ion (Ca++) channels, scn9A (sodium channel)
ascending signals are subject to descending modulation from the following neuroanatomical structures
somatosensory cortex, hypothalamus, peri-aqueductal grey, pons, prefrontal, anterior cingulate, - these descend by DLF (dorsal longitudinal fasciculus)
COMPLEX REGIONAL PAIN SYNDROME
type 1 - RSD - reflex sympathetic dystrophy, no evidence of actual tissue damage
type 2 -causalgia - has an identifiable etiology
treatment - sympathetic block and PT/OT.
a sympathetic block is determined to be successful in the the ipsilateral the skin temperature increases >1 degree C in the distrubution of the nerve. the temperature increases presumably because sympathetics are responsible for sweat, which cool the body by transfer of heat to H2O. side effect - horners syndrome
cervical blocks be aware - 0.5cc of of local into the vertebral artery is all that it takes to cause a seizure
don't do b/l cervical blocks because you can knock out the phrenic nerve
3 things to do to decrease ICP
1. hyperventilate
2. mannitol
3. steroids
acute increased in ICP only 1/3-1/2 will get papilledema
old tenet in medicine, "the real problem is greater than the potential problem"
i don't know if i agree with this all the time!
RENAL STUFF
PTH - catabolic for cortical bone, anabolic for trabecular
osteocalcin - blast marker
c-telopeptide - breakdown product of collagen, an osteoclast marker
alk phos - blast product (marker of mineralization) not metabolized by kidney
SIADH
A - erratic, greatly increased levels of ADH
B- constant ADH leak
C - osmostat reset
D -genetic increase in V2 aquaporin
etiologies of SIADH
cns - stroke, hemorrhage, infection, trauma, psychosis
malignancy - ectopic ADH secretion (usually in small cell lung ca) - a neuroendocrine tumor
drugs - carbamazepine, cyclyophosphamide, SSRI, valproate, ecstasy, interferons
surgery - 2/2 pain, can see triphasic presentation 1. polyuria, 2. siadh, 3. diabetes insipidus
pulmonary - pneumonia (viral bacteria tb)
hormone def - adrenal insufficiency and hypothyroid!!
hiv
treatment
free water restrict
salt tabs and furosemide (to wash out intramedullary gradient and prevent the ability to concentrate urine)
hypertonic saline (only in emergency hyponatremia)
classic blunder: giving IVF to siadh patient, anything fluid given is hypotonic to the patient's urine will only exacerbate free water retention
tolvaptan - V2 receptor antagonist
potent pimpable!
what is the differential diagnosis for increased BUN in the setting of normal GFR?
prerenal
catabolic process
high protein diet
GI bleed or other hemorrhage - (tissue destruction)
glucocorticoids (increases tissue destruction)
tetracycline therapy (decreasing tissue anabolism)
cystatin - a ubiquitous cysteine protease inhibitor looking to challenge creatinine as clinical measure of GFR
patient all of the sudden gone into A-FIB? don't forget about PE on your differential.
40 & 5, 40% O2 and 5cm PEEP - lowest vent settings (either coming off or going on)
1.23.2012
drug discovery review
preclinical drug discovery methods
screening by target
phenotype screening
natural substance modification
biologics
259 agents approved by FDA between '99-08
75 w/new molecular mechanisms of action
50 small molecules
25 biologics
28 were developed using phenotype screening
17 were developed using target based
drug discovery main focus since 1990's has been on targets - clone the receptor or protein and modify it, the rational basis
tools that aid the discovery of compounds - high throughput, x-ray crystallography, computational modelling/screening
prior to molecular era of the 90's was phenotypic screening - less emphasis on mechanism of action
pros/cons of target vs phenotypic screening
target based discovery
pro
hypothesis driven based on molecular/chemical knowledge, all biologics are discovered this way
con
the hypothesis is not useful because it is not involved in pathophysiology
phenotype screening
pro
do not need to know mechanism of action
cons
without mechanism, designing is difficult because don't know which properties to modify, also - screening can be less efficient (low throughput)
the following is a list of CNS drugs approved for these years (taken from their table), most do not have an identifiable target, and 3/7 do not have a known MMOA
Target MMOA
Levetiracetam unknown unknown
Memantine receptor receptor kinetics
rufinamide unknown unknown
varenicline ion channel partial agonist
zonisamide unknown unknown
ramelteon receptor equilibrium binding
discoveries by modification of natural substance
acamprosate ion channel modulator
term
biochemical efficiency - binding affinity/functional response (Ki/EC50)
28 of the first in class small molecules were identified with phenotypic screening -
25 were intentionally targeted, 3 incidentally discovered
MOA were reversed engineered after observing physiological phenomena
18/50 first in class molecules came from natural substances
ramelteon - a melatonin receptor agonist approved for insomnia was discovered with a target specific strategy.
biologics - large peptide molecules - all created using target based approach
enzyme replacement
novel functioning
inhibition of normal function
augmentation of normal function
phenotypic approach worked best for CNS and ID, target based approach worked well for cancer, ID, and metabolic disease