Log P, Log D, pka, pH Flashcards
What is pH a measure of?
H+ ion concentration = -log[H+]
Ka (meaning of large value?) and pKa
Ka = acid dissociation constant = [product]/[reactant].
Measure of strength of acid in solution
Large means products of dissociation is favoured
= strong acid
pKa = -logKa
- what does a high pKa for base mean?
2. what does high pKa for acid mean?
- high pKa base = strong base
2. high pKa acid = weak acid
Weak Acids
- pKa < pH of environment?
- pKa > pH of environment?
Weak Acids
- conjugate base (anion) form predominates
- environment is acidic so acidic (neutral) form predominates
Weak Bases
- pKa < pH of environment?
- pKa >pH of environment?
- environment basic (neutral) form predominates
- environment acidic (cation) predominates
weak bases tend to be absorbed in basic environments e.g. duodenum
Phenol pKa value and what this means for dissociation?
pKa=10
Ka= 10^-10 (acid dissociation constant)
Therefore 1 in every 10,000000000 molecules is dissociated
What is P and log P? What does it’s values mean?
log P = partition coefficient = a measure of lipophilicity in unionised form
P = [Co]/[Cw]
log p >0 = lipophilic
log p < 0 = hydrophilic
ionisation relation to solubility
ionisation increases hydrophilicity therefore solubility
hydrophobic groups - give 4 examples.
-CnHn- -Cl - Br - I
hydrophilic - give 2
COO- NH3+
log D
Positive?
log D = 2, meaning?
distribution coefficient takes into account ionised and unionised pH dependent and always less than log P \+ve means distribution in oil layer log D = 2, D = 100/1 = distribution in to 100x more lipid than water so lipophilic
log D equation
log D = log P + log Funionised
Funionised ACID = 1/(1+10^pH-pKa)
Multiple ionisable groups
log D must be calculated for all ionisable groups
Only +ve log D for all groups means absorption
pH of stomach?
small intestine?
2
8
pv = nrt
pressure x vol=no moles of gas x r x temp (kelvin)
+ve log D at pH with high bioavailability explanation?
Small intestine - massive surface area, absorption is favoured.
log D does not account for first pass
TPSA of well absorbed drugs threshold?
TPSA of BBB threshold?
<130 A^2 well-absorbed
<80A^2
Depot drug for monthly IM injections compared to oral daily?
log P increased so drug is retained in carrier and released slower
Why is one enantiomer more pharmacologically active than the other?
Ligand is chiral so stereoisomer binds with higher affinity
Advantages of salt administration?
Unionised/ionised?
Only hydrophilic form can dissolute in GI fluid generating single molecular entities for absorption across GIT cells.
Lipophilic = unionised -> absorbed
Bioavailability predicted by?
fraction absorbed from GIT but also first pass metabolism (amount in hepatic portal vein)
Which parameters influence amount filtered at Bowman's capsule? i = TPSA 36.3 ii = pKa = 8.9 iii = log P = 3.5 iv = oral F = 80% v = 80% plasma protein bound vi = V = 12 L/kg
v an vi = plasma protein determines how much free drug will be filtered. Bound drug cannot be removed
V determines how much is in blood. If drug is extensively distributed in tissues then the kidneys cannot access it
What health conditions could affect these parameters? i = TPSA 36.3 ii = pKa = 8.9 iii = log P = 3.5 iv = oral F = 80% v = 80% plasma protein bound vi = V = 12 L/kg
Renal failure
Obesity
Age
Hypoproteinemia
Half life of citalopram is 36 hours, why does it have a relatively long half life i = TPSA 36.3 ii = pKa = 8.9 iii = log P = 3.5 iv = oral F = 80% v = 80% plasma protein bound vi = V = 12 L/kg
V>0.7l/kg is very extensively distributed, heavily sequestered by tissues and fat. Organs slowly access for removal.
Kidney filtrate is also generally reabsorbed
