physiologic drug distribution and protein binding

what type of drugs can transverse cell membranes more easily?

• lipophilic drugs

• small molecules

most drugs enter cells by way of ….

• spontaneous passive diffusion

passive diffusion is governed by ….

• Fick’s Law of Diffusion

hydrostatic (Filtration) pressure is caused by capillary blood pressure being _____ than that of tissue at the arterial end

• high

T/F: PPB drug can cross membranes

• false

distribution may be ____ Limited or ____ Limited

• flow limited or diffusion limited

how does blood flow (Q) affect the first-order distribution constant (k)?

• direct correlation

  • increased blood flow = increased kd

how does the volume of the organ (V) affect the first-order distribution constant (k)?

• inverse correlation

  • increased volume of the organ = decreased kd

how does the Ratio of drug concentration in the organ to that in the venous blood (R) affect the first-order distribution constant (k)?

• inverse correlation

  • increased atio of drug concentration in the organ to that in the venous blood (R) = decreased kd

large blood flow (Q) (increases/decreases) distribution time

• decreases

a large volume (V) (increases/decreases) distribution time

• increases

how does increased accumulation affect elimination ½ life?

• causes long elimination half-life

what are the mechanisms of accumulaion

• dissolution in lipids

• reversible binding to biomolecules

• irreversible binding

• enzymatic or active transport

as the amount of free drug decreases, the dynamic equilibrium shifts to the ____

• left

reversible binding is usually due to ___ bonds like …

• weak bond

  • hydrogen bonds

  • van der waals forces

irreversible binding is usually due to ___ bonds like …

• strong bonds

  • covalent bonds

T/F: PPB drugs are not bioavailable

• true

T/F: drug-protein binding may be allosteric

• true

how does a “Depot” effect happen?

• “depot” effect = longer duration of action

  • increased PPB = longer elimination

what are the factors that affected protein binding?

1. drug properties (physicochemical properties)

2. protein properties + quantity of protein

3. drug protein affinity

4. drug-drug interactions

5. disease condition of patient

albumin is responsible for maintaining…

• osmotic pressure of blood

what type of drugs tend to bind to albumin?

• weak acid rugs

T/F: Albumin only has one binding site

• false

  • several binding sites that drugs can compete for

what type of drugs tend to bind to a1-acid glycoprotein (globulins) ?

• weak basic drugs

how does increased fraction of unbound drug affect volume of distribution?

• increased fraction of unbound drug = increased volume distribution

  • can diffuse more into tissues

how does PPB affect volume of distribution

• decreased penetration to targets of action in tissues

  • decreased Vd

the volume of distribution, f_u , and f_ut should only be measured under….

• equilibrium conditions

T/F: if PPB is actively secreted/eliminated, the elimination half-life can be short even with high protein binding

• true

what is non-restrictive elimination

• high PPB but still secretive because of active secretion / high intrinsic clearance in liver

  • elimination ½ life can be short

what is restrictive elimination?

• high PPB with long elimination ½ life

  • small hepatic extraction ratios (ER < f_u )

saturation can cause r __ n

• r = n

  • binding does not depend on number of amount of drug or amount of protein

r = n/2 when …

• [D] = k_d

what are the methods of determining K_a

1. double reciprocal plot

2. scatchard plot

the double reciprocal plot is one way to find the

a) K_a

b) [D]

c) r

d) n

a) K_a

The Scatchard plot is one way to find the

a) K_a

b) [D]

c) r

d) n

a) K_a

what does a non-linear plot suggest in a Scatchard plot

• there could be more than one type of binding site

what are factors that affect plasma concentration?

• protein synthesis

• protein catabolism

• distribution of albumin

• age

• disease

distribution of albumin in extravascular space ____ plasma protein concentration

• decreases

how are drugs highly PPB affected by small displacement

• small displacement can lead to large free drug released

  • increased ADE / increased toxicity

how does displacement affect V_d and t_1/2

• increased V_d

• longer t_1/2