Next Step: Make Cards on the Automatic Key Concepts, and Vignettes
Remember, the more you automatically know what each sentence means on your test, the better you will do. There are 4 stages in making interpretation more automatic:
- Stage 1: Unable to Make Pathophysiologic Chronologies in Either Timed or Untimed setting
- Stage 2: Basic Pathophysiologic Chronologies, but with Significant Gaps
- Stage 3: Detailed Pathophysiologic Chronology Without Time, but Unable to Consistently Generate PC During Timed Setting
- Stage 4: Consistent Pathophysiologic Chronologies in Timed Setting
My goal with these vignettes is to help you reach Stage 4. How do you do so?
- With the Automatic Key Concept cards, you can master the underlying information to move past Stages 1 + 2.
- Then, with the Vignette/Pathophysiologic Chronology cards, you can teach yourself to make these connections on your exam.
summary of key concepts:
Automatic Key Concepts:
Copy + paste these into your cards, to make these key concepts more automatic.
What are the chemical properties of things that diffuse across cell membranes passively (e.g., NOT a specific transport mechanism to aid it)?
Small (< 500-600 Da)
Lipophilic (log P often 2-4)
***It’s kind of fun to know that generally to cross membranes, the MW is < 500-600, the log P is 2-4, and things need to be uncharged.
Key point: a plasma membrane is a plasma membrane is a plasma membrane.
In other words, if something can cross one epithelial layer (skin, BBB, placenta, GI tract), there are excellent odds it can cross others
Let’s say we dissolve fentanyl in a water/octanol partition. If there were 10,000 molecules of fentanyl in the octanol layer, and 1 molecule in the water layer, what would the partition coefficient P be?
P = [solute]octanol / [solute]water = 10,000/1 = 10,000
Logarithmic scale – when is it typically used?
Most common usage is when there is a (very) wide range of values that need to be represented
For example, for computer integrated circuits, the transistors on early circuits were on the order of 1000s of transistors, whereas by the late 2010s they were on the range of 10,000,000,000
The cost of sequencing an entire genome was ~$100 million in 2001, but was only ~$1K by mid 2010s.
Log 1000 – what does this equal?
Recall: logb(x) = y, if by = x
Log 1000 = 3
(Log 1000 = Log10 1000 → 103 = 1000)
Log 100 – what does this equal?
Recall: logb(x) = y, if by = x
Log 100 = 2
(Log 100 = Log10 100 → 102 = 100)
If P = 10,000, what is log P?
Recall: logb(x) = y, if by = x
Log 10,000 = 4
(Log 10,000 = Log10 10,000 → 104 = 10,000)
Log P – use what it is to explain what values are typical for drugs that can cross membranes?
Log P = log ([solute]octanol / [solute]water)
If something is lipophilic it crosses membranes well, and will dissolve more in octanol than water.
Typical log P values for things that cross membranes are 2-4
(Note that because this is logarithmic, that means that the concentration would be 100 to 10,000x greater in the octanol layer than the aqueous layer)
Contraceptives that can be given as a patch / implant are based on what? Why does this make sense?
Estrogen / progesterone (or many steroid-hormone based therapies generally) can be given transdermally or as an injection. This is because the steroid hormones are based on the non-polar cholesterol, and can thus cross cell membranes → absorb through skin → enter systemic circulation
Heparin vs. warfarin – use their structure to explain which is contraindicated in pregnancy, and which can be taken orally?
Heparin ok, but not warfarin in pregnant women
Heparin = large/charged (very polar) → will NOT cross cell membranes, including the placenta and GI tract → CAN be given to pregnant women (but also can’t be given orally, since it will not be absorbed well by the GI tract)
Warfarin = small/nonpolar → WILL cross cell membranes, including the placenta and GI tract → CONTRAINDICATED in pregnant women (but can be given orally, since it will absorb well via the GI tract)
Steroid hormone receptors (e.g., progesterone, estrogen, etc.) – use what the hormones are derived from to explain the location of the receptors in/on a cell
Intracellular receptor – steroid hormones are cholesterol based (and thus non-polar, like cholesterol) → can cross cell membranes → receptor does NOT need to be on the cell surface (unlike peptides like insulin, or polar molecules like epinephrine/norepinephrine)
Neonatal hypothyroidism – use whether thyroid hormone can cross membranes to explain when testing is done
Testing for neonatal hypothyroidism performed at 2-4 days of age. Interesting, thyroid hormone, while small/lipophilic is charged at physiologic pH and so CANNOT diffuse across cell membranes. That said, there are specific thyroid transporters that facilitate diffusion so it CAN cross cell membranes, including placenta → maternal thyroid hormone can cross placenta and can thus mask a fetus’s inability to produce thyroid hormone → should test several days AFTER birth, to give time for maternal thyroid hormone levels to fall, so that thyroid hormone levels present would be made primarily from the neonate
Methylnaltrexone – use the chemical structure to explain what it is used for
Methylnaltrexone = quaternary (charged) version of naltrexone → poor GI absorption + doesn’t cross BBB treat peripheral opioid side-effects (used to treat opioid-induced constipation) without being absorbed systemically → won’t precipitate acute opioid withdrawal
Lactulose – use mechanism to explain what it is used for in cirrhosis
Used to treat hepatic encephalopathy
GI bacteria break down proteins → release the amine group from amino acids → NH3 (uncharged and can diffuse across the GI tract) → passive absorption
Lactulose – nonabsorbable sugar → metabolized by GI bacteria → produce H+ as a byproduct → convert NH3 to NH4+ → NH4+ is charged → does NOT passively diffuse across the GI tract → absorption of NH3 (toxic to cells, particularly brain cells) ↓
Physostigmine vs. neostigmine – use their structure to explain which can cross the blood-brain barrier
Neostigmine is a quaternary amine (and thus charged) → unable to cross BBB, whereas physostigmine is a tertiary amine (uncharged) → able to cross BBB
Cholestasis – would urine be lighter or darker than usual? Why?
Darker. Cholestasis → conjugated (water-soluble) bilirubin reflux back to liver → leaks into bloodstream → stays dissolved in plasma as it is filtered by kidneys → conjugated bilirubin in urine ↑ → dark urine
Fentanyl vs. morphine – which will have a higher volume of distribution? Why?
Fentanyl has a (much) higher volume of distribution
Fentanyl is highly lipophilic → distributes widely to fat → low amount left dissolved in serum → serum concentration ↓ → Vd ↑ (recall Vd = drug dose / serum concentration, so if serum concentration ↓ → Vd ↑)
In contrast, morphine is highly water soluble → does NOT distribute to fat, but stays constrained to water compartments
Liver vs. kidney drug elimination – which property affects where drugs are eliminated/metabolized? Why does this make sense?
Lipophilic drugs metabolized by the liver; hydrophilic drugs metabolized by the kidneys
Kidneys – water-soluble drugs stays dissolved in the serum → filtered through glomerulus → eliminated via kidneys
Liver – fat-soluble drugs often bound to albumin or other plasma proteins → since albumin is not filtered, the drugs are not filtered → stay in blood and ultimately end up in liver → liver elimination
Michelene T. H. Chi, Paul J. Feltovich, and Robert Glaser, “Categorization and Representation of Physics Problems by Experts and Novices,” Cognitive Science 5, no. 2 (April 1981): 121–52, https://onlinelibrary.wiley.com/doi/pdf/10.1207/s15516709cog0502_2.
Mass spring.svg. (2014, December 27). Wikimedia Commons, the free media repository. Retrieved 18:58, August 5, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Mass_spring.svg&oldid=144270432
Atwood.svg. (2020, May 1). Wikimedia Commons, the free media repository. Retrieved 18:58, August 5, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Atwood.svg&oldid=416270903
Leung AM. Thyroid function in pregnancy. J Trace Elem Med Biol. 2012;26(2-3):137-140. doi:10.1016/j.jtemb.2012.03.004
Visser TJ. Cellular Uptake of Thyroid Hormones. [Updated 2016 Jun 15]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285565/
Separatory funnel with oil and colored water.jpg. (2020, October 27). Wikimedia Commons, the free media repository. Retrieved 18:04, December 29, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Separatory_funnel_with_oil_and_colored_water.jpg&oldid=504066875.
Moore’s Law Transistor Count 1971-2018.png. (2020, October 31). Wikimedia Commons, the free media repository. Retrieved 19:13, December 29, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Moore%27s_Law_Transistor_Count_1971-2018.png&oldid=508619247.
Cost per Genome.png. (2020, October 1). Wikimedia Commons, the free media repository. Retrieved 19:16, December 29, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Cost_per_Genome.png&oldid=477678094.
Log P examples 01.png. (2020, October 29). Wikimedia Commons, the free media repository. Retrieved 19:27, December 29, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Log_P_examples_01.png&oldid=506508687