Summative 1

ΔH < 0

enthalpy = interaction energy that increases when bonds form

exothermic = heat released (↑T)

favorable bc releases thermal heat to surroundings

ex. drug-target binding

ΔH > 0

endothermic = heat absorbed (↓T)

unfavored, unless large enough S

bonds break

ex. dissolution, melting

S

entropy

disorder and microstates, #microscopic arrangements (W)

favorable when ΔS > 0

increased disorder = more accessible configurations = more favorable

ΔG = ΔH – TΔS

Gibb’s free energy

predicts whether rxn occurs (negative, system drops to more stable state) or doesn’t (positive, will not progress forwards on its own)
ΔG = 0 dynamic equilibrium

ΔG = –RTlnK

how far rxn will proceed before stalling

K = equilibrium constant, ratio of P:R at equilibrium

ΔG < 0 makes K > 1, so product-favored (negative = rxn occurs)

ΔG > 0 makes K < 1, so reactant-favored (positive = rxn does not occur)

pH = pKa + log[A–]/[HA]

steps:

1. given pH and pKa

2. solve for x = [A–]/[HA]

3. %prot = 1 / (1 + x)

weak bases (high pKa) + ↓extracellular pH (more acidic) = ↑protonation = ↑hydrophilic = ↑electrostatic interactions with extracellular water (that traps molecules in shells) + membranes favor like hydrophobic = ↓entry into tumor cells

ion trapping

hydrophobic (uncharged) molecule enters cell favorably

pH changes from extracellular to intracellular = (de)protonates = becomes hydrophilic = cannot exit cell

partition coefficient (P)

ratio of [drug in lipid phase (octanol)] to [drug in aqueous phase (water)]

can be large values = use logP

large logP = hydrophobic drug, bc more in lipid phase = cross membranes ↑readily

small logP = hydrophilic drug, bc more in aqueous phase = ↑aqueous solubility + requires membrane transporters

amount = concentration • volume

effective drugs balance both hydrophilicity to dissolve in blood + hydrophobicity to enter cells and bind to target via hydrophobic effect

why do hydrophobic drugs prefer octanol?

water cannot form hydrogen bonds with NP hydrophobic surfaces

= water forms “cages” around drugs = entropically disfavored bc drug doesn’t dissolve

= drug gets pushed into lipid phase via hydrophobic effect

tissue types

1. epithelial

   1. covers body surfaces

   2. lines cavities

   3. forms glands

   4. closely packed sheets of cells

2. connective

   1. binds/supports/protects organs

   2. mostly ECM

3. muscle

   1. generates movement

   2. excitable/contractile tissue

4. nervous

   1. transmits signals throughout body via neurons

   2. optimized for high-speed electrical/chemical signal transmission

oral drug pathway, first-pass effect

1. oral cavity (mouth)

2. pharynx

3. esophagus

4. stomach

5. SI (duodenum, jejunum, ileum)

6. absorption

   1. intestinal epithelium (simple columnar, microvilli)

   2. lamina propria (loose connective, some BVs)

   3. capillary endothelium (simple squamous, thin wall of intestinal capillaries)

7. intestinal capillaries

8. hepatic portal vein

9. liver (metabolism/detoxify)

10. hepatic veins

11. IVC

12. RA/RV

13. pulmonary arteries

14. lungs (oxygenate)

15. pulmonary veins

16. LA/LV

17. aorta

18. systemic arteries

IV drug pathway

1. median cubital vein

2. axillary vein

3. brachiocephalic vein

4. SVC

5. RA/RV

6. pulmonary arteries

7. lungs (oxygenate)

8. pulmonary veins

9. LA/LV

10. aorta

11. systemic arteries

bypasses portal circulation

excretion via urine

if hydrophilic (polar, charged)

1. systemic arteries

2. renal artery

3. kidneys

4. ureter

5. urinary bladder

6. urethra

excretion via feces

if hydrophobic (NP, uncharged)

1. systemic arteries

2. hepatic artery

3. liver (bile production)

4. gallbladder (bile storage)

5. common bile duct

6. SI (duodenum, jejunum, ileum)

7. LI (cecum, ascending/transverse/descending/sigmoid colon)

8. rectum

9. anus

histology of blood vessels

1. arteries

   1. smooth endothelium

   2. internal elastic lining to handle strong P

   3. ↑smooth muscle + ↓outer connective tissue

2. capillaries

   1. simple squamous = thin endothelial cell layer

   2. rests on delicate basement membrane

   3. allows for nutrient/gas exchange

3. veins

   1. endothelium containing internal folding modifications = 1-way valve to prevent backflow

   2. ↓smooth muscle + ↑outer connective tissue

GI functions of:

1. stomach

2. liver

3. gallbladder

4. pancreas

5. jejunum/ileum

6. large intestine

1. acid/mechanical digestion

2. metabolize blood, produce bile, store glycogen, produce plasma proteins

3. store/secrete bile

4. produce digestive enzymes, insulin, glucagon, somatostatin

5. reabsorb water/electrolytes, eliminate waste

fraction of bound DR at equilibrium

[D] = concentration • (V of drug / V total mixture)

[R] = concentration • (V or receptor / V total mixture)

Kd = ([D] – x)([R] – x) / x

solve for x to get [DR] at equilibrium

amount of [D] needed, to have 99% [DR] at equilibrium

f = [D] / ([D] + Kd)

f = 0.99

solve for [D]

hydrophilicity vs hydrophobicity of atorvastatin

hydrophilicity:

• electrostatic interactions (ionic/hydrogen bonds) with HMGR

• ↑specificity to identify/position onto HMGR

hydrophobicity:

• fits into hydrophobic pocket of HMGR

• hydrophobic effect:

  • before bind = disfavored water cages around hydrophobic regions

  • after bind = displaces water

• = increases entropic favoring

  • major driving force for tight binding

  • also allows VDW to help drug block HMGR