Asmah Nasser, M.D.

PharmacokineticsPharmacokinetics is the quantitative study of drug movement in, through and out of the body

What Happens After Drug Administration?Absorption Distribution MetabolismElimination /Excretion

Important factors to knowFactors affecting absorption Concept of ionization , pKa and pHHenderson Hassel Balch equationBioavailability , Bioequivalence , AUCDistribution , volume of distribution (Vd), redistributionPlasma protein binding

Important factors to knowMetabolism (biotransformation) , CYP 450 etcExcretionFirst and zero order kinetics of eliminationPlasma Half life ClearanceSteady state ,loading and maintenance doseTherapeutic drug monitoring Pharmacokinetic calculations

AbsorptionAfter a drug is administered, how does it reaches site of action? Absorption is the transfer of a drug from its site of administration to the blood stream. In order to reach their site of action, a drug has to pass through several membranes

TransportA. Passive diffusion: Concentration gradient across membrane is the driving force for movement of drug molecule across the membrane Small size, water soluble drug molecule penetrate through aqueous channels or paracellular spaces Filtration few drugs does this Lipid soluble drugs readily pass through membrane by dissolving in membrane .many drugs does this B. Active Transport:Movement occurs against the concentration gradient and needs energy like ATP

Factors that affects absorptionThe particle size Smaller is betterconcentration gradient Surface area and vascularity of that areaLipid solubility / Water solubility Nature of the drugacidic or basicIonized or non ionized The pH levels on either side of cell membrane pKa of the drug

Lipid/Water solubilityOnce in solution, drugs exist as a mixture of two interchangeable forms1. Water-soluble is the ionized or electrically charged formCannot cross membrane 2. Lipid-soluble is the non ionized, or uncharged form.Can cross membrane

Concept of ionizationcontinued We know most of the drugs are either weak acid or a weak base and when dissolved in body fluids, some or all of a drugs molecules become ionized/unionized

* HA H+ + A- BH+B + H+

Concept of ionizationcontinuedWhat percentage is ionized /unionized determined by following factors :1.Whether the drug was an acid or a base.2. Whether it is dissolved in an acid or base medium (Eg: Stomach or intestine ?) i.e pH of the medium.3. And also the pKa of the drug.

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Role of pH in ionization of a Weak base As pH increases, a weak base will become more and more unionized, lipid soluble and better absorbedAs pH decreases, a weak base will become more and more ionized, lipid insoluble, and will not be absorbed. Also becomes more water soluble and better excreted.

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* pH of the medium 100%50%0%175%25%Role of pH in ionization of a Weak base % of Unionized form14

As pH increases, a weak acid will become more and more ionized , lipid insoluble and will not be absorbed. Also becomes more water soluble and better excreted .As pH decreases, a weak acid will become more and more unionized , lipid soluble and better absorbed .

*Role of pH on ionization of a Weak Acid

* pH of the medium 100%50%0%175%25%Role of pH in ionization of a Weak acid% of Unionized form14

QuestionAspirin is an acidic drug.In the stomach, is it mostly in the ionized or unionized form?

Moral of the story...Acidic drugs are Absorbed best in Acidic environments

*Basic drugs are Best absorbed in Basic environments

So...*To absorption of an basic drugacidify the environment

To absorption of an acidic drugalkalanize the environment...This concept is very important in treatment of a drug poisoning

pKapKa is equivalent to the pH at which 50% drug is ionized and 50% is unionized.Remember this point pKa Is the negative logarithm of acidic disassociation constant of the weak electrolyte not necessary to know*

* pH of the medium 100%50%0%175%25%pKa % of Unionized form14

Henderson-Hasselbalch equation

The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation

The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pKa and the pH of the medium as follows:*

Henderson-Hasselbalch equation

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pH-pKa-2-10+1+2Weak acid: %nonionized9990501001Weak base: %nonionized0110509099

Question1. The pKa of acetylsalicylic acid is 3.5. What percentage of the drug is in an absorbable form in the stomach at pH of 1.5? A. 0.1% B. 1% C. 10% D. 90% E. 99

QuestionThe greater proportion of the dose of a drug administered orally will be absorbed in the small intestine. However, on the assumption that passive transport of the nonionized form of a drug determines its rate of absorption, which of the following compounds will be absorbed to the least extent in the stomach?a. Ampicillin (pKa = 2.5)b. Aspirin (pKa = 3.0)c. Warfarin (pKa = 5.0)d. Phenobarbital (pKa = 7.4)e. Propranolol (pKa = 9.4)

SummaryA drug molecule carrying an electrical charge is said to be IonizedLipid-soluble is the non ionized, or uncharged form.Can cross membranePercentage of ionized drug depends on :1.Whether the drug was an acid or a base2. Whether it is dissolved in an acid or base medium (Stomach or intestine ?) i.e pH3. And also the pKa of the drug As pH increases, a weak base will become more and more unionized ,lipid soluble and better absorbedAs pH decreases, a weak acid will become more and more unionized ,lipid soluble and better absorbed

SummarypKa is equivalent to the pH at which 50% drug is ionized and 50% is unionizedFor a weak acid if pH pKa is low it will be more nonionized and better absorbedFor a weak base if pH pKa value is high it will be more nonionized and better absorbed

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