Lecture 4 Drug-Receptor Interaction

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11 Apr 2012

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PCL 201 – Lecture 4
Ionization is particularly important, our physiological system is aqueous, water is abundant
and can form dipoles and dissociate to interact with particular compounds.
Acidic Drugs
HA H+ + A-
acidic environment, forced to right
weak acids will be protonated
XH X + H+
deprotonated form more lipid soluble at low pH
Rule of thumb: to roughly calculate percent ionization based on pKa value of drug
and pH of compartment.
Ionization affects drug distribution.
At physiological pH, morphine is ionized but fentanyl is not, so it can access brain
more rapidly and is more potent.
Range of pH values in different compartments.
Blood 7.4 (We have an effective buffer system)
Urine can change more substantially (5-8); can be changed by diet; vegetarians tend to
have more basic urine. High protein diets have more acidic urine.
Small intestine 8
Stomach 2
Ionization is important for absorption and distribution, reaching a particular target.
Compartment pH plays a role
Protonated compound (charged), less lipid soluble
Law of mass action: one molecule crosses membrane (unionized), another molecule will
become unionized. This occurs more rapidly in compounds with less percent ionization.
Reaction is forced, allowing more molecules to cross membrane. Least amount of
ionization more readily available.
e.g. 99.95% vs. 99.99%
Compounds should not be highly ionized - absorption and distribution will be limited.
Drug overdoses and poisoning - you can target/trap drugs in a particular compartment.
Changing pH of urine - Drug Trapping - You can increase secretion of a drug
Weak Acid drugs excreted faster in alkaline urine
Weak Base drugs excreted faster in acidic urine (they are charged)
Rational drug design - creation of a drug that is absorbed in a particular route
Too lipophilic - can't cross stagnant water layer outside cell membrane.
Drug interactions with protein can occur through a number of different interactions.
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