Chemistry Respiratory Disorders Flashcards
Hydrophobicity
effects the ability of the drug molecule to cross cell membranes and/or perform a suitable binding interaction
The partition coefficient
P = [Drug]Octanol / [Drug]Aqueous
High P =
High P = hydrophobic compound
Low P =
Low P = hydrophilic compound
Lipophilicity (log P)
Substituent hydrophobicity constant, π
§ Is a measure of how hydrophobic a substituent is, relative to hydrogen
§ It allows the partition coefficient, for a particular compound, to be calculated (rather than being measured experimentally)
positive π value
A positive value = more hydrophobic than hydrogen
negative π value
A negative value = less hydrophobic than hydrogen
The importance of pKa
o Drug absorption is determined by solubility, molecular weight and the degree of ionisation
o The local pH will dictate the degree of drug ionisation
o The pH at the mucosal surface is 7.39
pKa values for weak acids (HA) that exceed 10 to11 = little, if any, anionic contribution in the pH ranges used in pharmaceutical formulations and in the physiological pH ranges.
Similarly, pKa values for the conjugate acid of a weak base (BH+) that are below 2 to 3 = little, if any cationic contribution.
pKa graph
The pKa of the acid is the pH where it is exactly half dissociated
alcohols are..
weak acids
For a weak acid, HA
o At a pH above its pKa the acid exists mostly as A–
o At a pH below its pKa the acid exists mostly as HA (unionised)
For a weak base, B
o At a pH above its pKa the base exists mostly as B (unionised)
o At a pH below its pKa the base exists mostly as BH+
The more stable the conjugate
base,
The more stable the conjugate base, the stronger the acid
drugs to treat asthma
nitrogen is the most basic group
Drugs to treat asthma…
Muscarinic antagonists
- A quaternary ammonium derivative of atropine
- Stable in neutral and acidic solution, but rapidly hydrolysed in alkaline solutions.
- Drug effects last for about 6h. eg atropine
Tiotropium
thiapine s membered ring is aromatic and can remove chirality at the centre
Log P = -0.86
Drugs to prevent asthma… LABA - salmeterol
- Contains a N-phenylbutoxyhexyl substituent
- Associates slowly with β2-receptors resulting in slow onset
- Dissociates at an even slower rate
- Resistant to both MAO & COMT
- Very long acting (12h), which is attributed to the highly lipophilic phenylalkyl substituent
- The R isomer of phenylethanolamines possesses the activity
Drugs to prevent asthma… LABA - formoterol
- Contains a 3’-formylamino group & 2 chiral centres!
- No clinical advantage of using optically pure material due to high potency and low dose required - so racemate is used
- Much faster onset than salmeterol due to lower lipophilicity
- Very long acting (12h) which is comparable to salmeterol
Drugs to prevent asthma… methylxanthines - therophylline
- Contains the xanthine alkaloid structure
- Naturally occurring (found in tea)
- Less lipophilic than caffeine
- NH provides Brønsted acid potential and imino N provides Brønsted base potential
what increases lipophilicity
more carbons
what is a formyl group
formyl is a aldehyde attached to amine
which group has a low log p
Fluro
which group has a high log p
Chloro
what doesnt have a pka
a weak base
what effects whether it is predominantly ionised or un-ionised
the environment
more resonance forms means
higher stability
S and R configuration
S is anticlockwise and R is clockwise configuration
Drugs to treat asthma examples
o β2-adrenoceptor agonists
o Muscarinic antagonists
Drugs to prevent asthma examples
o Long-acting β2-adrenoceptor agonists (LABAs)
o Methylxanthines
o Glucocorticoids
o Leukotriene receptor antagonists
