DDDistribution

Question 1

Why might a drug not be able to pass through membranes?

Answer 1

Too large; protein bound; highly charged; or high water solubility

Question 2

What are implications for drugs that can’t pass through membranes? At GI mucosa? At BBB/placenta? At renal tubules?

Answer 2

These areas all have tight junctions so drugs cannot go between cells (have to go through membranes). At GI mucosa there will be negligible absorption if drug is administered orally. BBB/placenta: Limited distribution of drug from blood into brain or into fetal circulation. Renal tubules: Following filtration at glomerulus (note that large or protein bound drugs are not filtered); reduced reabsorption of drug back into blood; thus enhancing excretion via urine

Question 3

Essential difference btwn an acid and a base

Answer 3

Dissociation of a proton from an acid produces an ionized drug; whereas dissociation of a proton from a base produces an unionized drug (HA H+ + A- vs. BH+ H+ + B

Question 4

When do acids become nonionized?

Answer 4

In an acid medium

Question 5

When do bases become non-ionized?

Answer 5

In alkaline medium

Question 6

Which form of a drug is more readily absorbable?

Answer 6

Non-ionized forms. Ionized forms do not cross lipid membranes

Question 7

Rule of thumb when tissue pH is lower than pKa of the drug

Answer 7

There are relatively more protons and the PROTONATED form of the weak acid [unionized-lipophilic] or weak base [ionized] drug will predominate

Question 8

Rule of thumb when tissue pH is higher than pKa of the drug

Answer 8

There are relatively fewer protons and the UNPROTONATED form of the weak acid [ionized-hydrophilic] or weak base [unionizedlipophilic] drug will predominate

Question 9

Ion trapping

Answer 9

At equilibrium unionized concentration of drug is the same on both sides of the membrane BUT TOTAL concentration of drug is greater on side where ionization is greater - drugs are trapped where they are predominantly ionized. I.e. Acidic drugs get trapped in more basic solution. Basic drugs get trapped in more acidic solutions. (If predominant form on both sides is non-ionized; ion trapping will be relatively insignificant)

Question 10

Which protein primarily binds acidic drugs?

Answer 10

Albumin

Question 11

Which protein primarily binds basic drugs?

Answer 11

alpha-1 acid glycoprotein

Question 12

Effects of drug binding to protein

Answer 12

Reduces concentration of active/free drug (can limit fetal exposure to drugs). Hinders metabolic degradation and reduce rate of excretion (will decrease elimination rate and increase half-life) i.e. acts as circulating drug reservoir that can prolong drug action. Decreases volume of distribution by enhancing apparent solubility in blood. Decreases ability to enter CNS across blood brain barrier

Question 13

Volume of distribution

Answer 13

Vd = Amount of drug in body (dose) / Concentration of drug in plasma (Cp). The volume of the body fluids into which the drug distributes following its administration.

Question 14

What is the Vd for drugs that are highly bound to plasma proteins?

Answer 14

Somewhere around the volume of plasma/blood (3-5 L). EX Heparin Vd = 4 L; Warfarin Vd=10 L

Question 15

What is the Vd for drugs that are highly water soluble and enter cells poorly?

Answer 15

Somewhere around the volume of extracellular water (12 - 15L). EX ibuprofen Vd = 11L

Question 16

What is the Vd for drugs that freely enter cells?

Answer 16

Somewhere around the amount of total body water (42 L). EX Lithium Vd= 46 L; ethanol Vd = 42 L

Question 17

Can Vd be much higher than the total body water?

Answer 17

Yes; if the drug gets sequestered at specifc sites: CNS/fat/protein. Often these drugs are highly lipid soluble.

Question 18

Equation for plasma concentration; lose and volume of distribution

Answer 18

Cp = D/(Vd)

Question 19

Equation for loading dose (LD); desired plasma concentration and volume of distribution

Answer 19

LD = Cp (desired) x Vd