Transcript Introduction to Pharmacology

Pharmacokinetic Principles and
Drug Excretion
September 7, 2007
Frank F. Vincenzi
Learning objectives
• Principles of active and
passive permeation of
membranes
• Effects of lipophilicity,
pH and pKa on
absorption, distribution
and excretion of drugs
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Filtration
Secretion
Reabsorption
Excretion
Creatinine clearance
Glomerular filtration rate
probenecid
Major processes of
pharmacokinetic interest
• Absorption
• Distribution
• Metabolism (also called biotransformation)
• Elimination (by biotransformation &/or excretion)
Drug ADME
(absorption, distribution, metabolism & excretion)
Permeation of drugs through membranes
Specialized
permeation
processes for
molecules across
membranes
(includes
neurotransmitter
release and
recycling of
membrane
vesicles)
Most drug absorption, distribution &
excretion depends on:
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Surface area
Blood flow
pH
Physico-chemical properties of the drug
Fick’s law:
flux (molecules/time) =
(C1 - C2) * (area) *(Permeability coefficient)/(thickness)
Route of administration: Surface area and
blood flow affects drug absorption
• Lungs - tennis court (total cardiac output)
• GI tract - Intestine >> stomach (blood to portal system)
• …[other routes of drug administration?]
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Intramuscular (IM) (greater blood flow than)
Subcutaneous (SubQ)
...
Nasopharynx
Eye
Typical pH values of drug-absorbing
membrane surfaces
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Gastric
Duodenal
Jejunal & Ileal
Colon
Buccal
Urethral
Vaginal
Conjunctival
1.0 - 3.0
4.8 - 8.2
7.5 - 8.0
7.0 - 7.5
6.2 - 7.2
5.0 - 7.0
3.4 - 4.2
7.3 - 8.0
Definition of pH
• -log of molar concentration of [ H+]
• water, pH = 7
• 0.1 M HCl, pH = 1 (assuming complete
ionization)
Henderson-Hasselbach made simple:
pKa - pH = log ((protonated)/(non-protonated))
When pKa = pH, then log ((50)/(50)) = log(1) = 0
• Acidic (HA and BH+)
• Basic (A- and B)
ratio protonated:non-prot.
ratio protonated:non-prot.
1 ~ 90:10
2 ~ 99:1
3 ~ 99.9:0.1
4 ~ 99.99:0.01
-1 ~ 10:90
-2 ~ 1:99
-3 ~ 0.1:99.9
-4 ~ 0.01:99.99
Why do weak acids tend to be rapidly absorbed from
the stomach?
Why do weak bases tend to ‘ion trap’ in the
stomach?
Why, after they are given by mouth, do most
drugs tend to absorb mainly from the
intestine?
•Fick’s law:
flux (molecules/time) =
(C1 - C2) * (area) *(Permeability coefficient)/(thickness)
General
determinants
of drug
distribution
Useful generalizations about drug excretion:
• Lipid soluble compounds tend to be metabolized
to more water soluble products before being
excreted (unless they are metabolized, they may
not be excreted)
• Water soluble compounds tend to be excreted by
the kidneys (urine is mainly water)
Fundamental processes in
the kidney nephron:
Excretion = filtration + secretion reabsorption
Water filtered is about 190 liters/day;
excreted is about 1.8 liters/day. About
99% reabsorption
AND
as water is reabsorbed the
concentrations of solutes in the tubule
increases…….this tends to promote
passive reabsorption
excretion
A general rule:
• Unless protein bound, most drugs are
filtered by the glomerulus
• If filtered, and unless reabsorbed, half of the
drug in the body is eliminated by the
kidneys in an hour or so. If also secreted,
elimination may be faster.
Creatinine clearance (CLCR)
• Creatinine is a normal product of muscle
metabolism.
• Creatinine is filtered in the kidney
glomerulus; it is neither secreted nor
reabsorbed. (Well…secreted just a little)
• CLCR is therefore used as a rough estimate
of the glomerular filtration rate
Some drugs are secreted
• Penicillins
• Probenecid (inhibitor of the anion pump
mechanism in kidney tubules) can inhibit secretion
of other compounds, for example, penicillin [it can
also inhibit the reabsorption of uric acid - which is
its basis in the treatment of gout]
• Para-amino-hippuric acid (PAH)
Most drugs are partially reabsorbed
• Hydrophilic (water soluble) drugs tend to remain
in tubular urine as it becomes concentrated
• Lipophilic (lipid soluble) drugs tend to be
reabsorbed as tubular urine is concentrated.
Permeation of drugs through membranes
Percent ionization of drugs at different pH values
Drug X
Alkaline diuresis (14 grams NaHCO3 in 1 liter, IV) increases
phenobarbital (Pb, pKa = 7.2) excretion in a 70 kg human volunteer
Adapted from Waddell & Butler, JCI 36: 1217-1226, 1957