PCL201H1 Lecture Notes - Lecture 3: Hydrogen Bond, Acid Dissociation Constant, Alkanolamine

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11 Jan 2018
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Physiochemical Properties
To extern effect must be absorbed, distribute, reach site, be eliminated
Define by drug’s properties and membrane characteristics
Must be able to traverse water
Molecular size
Mostly 500 Da, proteins at 6 kDa, 65 kDa
Limiting to water soluble
Solubility
Nature of solvent
Hydrophilic
Hydration shield, lipids use carriers
Energy to cross membranes
Lipophilic
Membrane permeability
Bioaccumulation
Too lipophilic may mean less absorption, cut off
Non polar: hydrocarbons
Intermediate: carbonyl, ether
Polar: alcohols, amines
Very polar: amino alcohol, hydroxyl acids
Amphipathic: both regions
Pow: high = lipid solubility, LogP is log of Pow
Drugs typically 0.5-5 LogP
Ionization
Unionized can cross
Depends on pKa, pH, and if acid or base
Acids ionized at high pH
pKa nothing about acid or base
Diazepam 3.4 and is a base
Solubility, permeation, elimination, binding
Affect absorption
Trapping: trap acids by alkalizing, trap bases by acidifying
Affects drug design
pH - pKa
ACIDS
BASES
Fluid
-3
0.1
99.9
Blood - 7.4
-2
1
99
Urine - 5-8
-1
10
90
Sm intestine - 7.5-8
0
50
50
Stomach - 2-3
1
90
10
Prostate - 6.45-7.4
2
99
1
Vaginal - 3.4-4.2
3
99.9
0.1
Lipinski’s Rule of 5
log P < 5
Mw < 500 Da
<10 hydrogen bond acceptors
<5 hydrogen bond donors
Violation may result in oral bioavailability
complications
<140 A2 TPSA (<90 for brain)
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