PCL201 Lec 5-8

Reservoirs that could alter V_d

intravascular plasma proteins

extravascular (tissue binding/accumulation)

adipose tissue (low blood flow to fat, long time to be removed)

enterohepatic circulation (first pass metabolism)

disease states

intravascular proteins affecting V_d

drugs may associate with blood components (mainly albumin)

only unbound drug molecules can diffuse and exert pharmacological effect, subject to elimination

small water soluble compounds

may pass between cells in some tissues (depends on the barrier)

small molecules can utilize aquaporin channels

lipid soluble molecule diffusion

compound must diffuse across bilipid membrane

rate of diffusion depends on:

drug concentration

P_ow

degree of ionization

surface area of membrane (small intestine has the greatest area, most drugs are absorbed here regardless of ionization. rate of drug absorption is related to rate of stomach emptying)

facilitated diffusion

eg amino acids into brain, bile salts into liver, nucleotide analogs or anti-metabolites

Transport proteins

can be primary, secondary transport, or facilitated

can increase drug absorption and distribution

uptake transporters, and efflux transporters

transcytosis

endo and exocytosis

total body water

~60%

40% in intracellular fluid

20% in ECF

total body water definition

the total water content of the body. varies depending on body composition, age, and gender.

small molecules like ethanol and some antibiotics equilibrate with TBW

extracellular fluids

water outside of cells

intravascular fluid (plasma) + interstitial fluid (bathing cells)

drug distribution to ECF is very important, many drugs act on cell surface receptors

many drugs distribute through ECF quicker than they permeate membranes, so the onset of action is faster if the drug acts on cell surface than if the site of action is within cells

hematocrit

% of red blood cells.

tissue localization

tissue-specific binding sites can retain drug in that tissue

highly lipid soluble drugs can localize and accumulate in adipose in tissue

results in uneven distribution of drug

drug is retained in the body for longer periods of time

volume of distribution (actual)

anatomical volume accessible to the drug

volume of distribution (apparent)

the hypothetical volume of plasma into which the drug appears to distribute

a drug that distributes in TBW has a low plasma concentration and therefore a large V_d

volume of distribution equation

V_d = dose / plasma conc

High V_d

drug is in extra vascular tissues and distributed in TBW (low plasma concentration)

not homogenously distributed

Low V_d

drug distrbutes to ECF only or plasma only - has a higher plasma concentration

retained within the vascular compartment

extensive binding to plasma proteins, or large hydrophilic molecules

dissociation constant K_d

1/affinity

% free drug depends on

K_d of drug

total drug concentration (saturated binding sites)

albumin concentration

Low K_d

High affinity. drug is mostly bound at low drug concentrations

drug-plasma protein binding effect on decreasing elimination

bound drug may not be eliminated as readily

protected from filtration at kidney and cannot enter hepatocytes by passive diffusion

drug-plasma protein binding effect on increasing elimination

drugs that are eliminated by active mechanisms (transporters) are generally not limited by binding

drug -protein as a reservoir

protein-drug complexes can prolong duration of action because of decreased elimination. lower max intensity

determinants of drug-plasma protein binding

physicochemical properties of drug

age (low in elderly)

disease states

competition between drug and endogenous compounds

drug-drug interactions (compete for binding)

extravascular drug-tissue binding

drugs may selectively bind to macromolecules (proteins) and accumulate in certain tissues

slow release of drug, accumulation. prolonged half-life and duration of action

may be the basis for pharmacological action - macromolecule may be a receptor or enzyme target

tissue accumulation might be toxic

enterohepatic circulation

drugs extracted from circulation by liver can be reabsorbed across intestinal mucosa back into blood, acting as a potential drug reservoirper

perfusion rate

blood is rapidly distributed to highly perfused organs (liver, kidney, heart)

perfusion rates change during exercise, increased perfusion of musculature

drug clearance

volume / unit time

how much biological fluid from which a drug can be completely cleared in a given unit of time

does NOT indicate the amount of drug being removed

fat soluble drugs are biotransformed to water-soluble metabolites to be excreted

total body clearance (TBC)

removed by liver, kidneys, lungs, and GI tract. also sweat and feces

TBC = CL_hepatic + CL_Kidneys + CL_lung …

termination of drug action

1. enzyme mediated inactivation (metabolism / biotransformation). primarily in the liver

2. removal / excretion. primarily by the kidney, some in bile, breath, sweat. includes unchanged drug and metabolites if it’s already polar/water soluble

zero order elimination

rate of elimination is constant. elimination mechanism is “saturated”. constant amount eliminated per unit time

first order elimination

constant fraction eliminated per unit time

elimination rate constant (k)

-slope x 2.3

half-life

0.693/k

total body clearance

k x V_d

dose / AUC

Cl_organ

QE

perfusion rate x extraction rate

E

(C_in - C_out) / C_in

between 0 and 1. >0.7 is high

determines to what extent Cl is affected by blood flow, plasma protein binding, and intrinsic ability of the liver

High E drugs

the drug is effectively extracted,

Cl is sensitive to hemodynamic changes

protein binding will not decrease Cl,

small variation in enzyme function will not significantly alter Cl

hepatic clearance

major route of clearance for lipophilic drugs

via hepatic metabolism (dependent on hepatic blood flow and hepatic extraction ratio)

and biliary excretion (transporting from hepatocytes into bile. active process, polar compounds. may be competitively inhibited, enterohepatic circulation may occur)

biliary clearance Cl_B

(bile flow x C_b) / C_p

_{bile flow is around 0.5-0.8 mL/min}

intrinsic hepatic clearance

maximum ability of liver to eliminate drug from blood in the absence of other confounding factors like protein binding and blood flow

F_H - bioavailability after extraction

1-E

AUC(oral) / (AUC) IV

factors affecting Cl_H

State of liver (age, disease)

Presence of other drugs/agents (inhibitors reducing enzyme activity, inducers increasing enzyme activity)

Blood Flow (Q)

Renal clearance Cl_R

major route for polar drugs and metabolites

C_u x Urine Flow / C_in

glomerular filtration

driven by hydrostatic pressure across a selectively permeable capiillary

<2000 Da drugs are filtered, only unbound drugs

glomerular filtration rate (GFR) ~120 mL/min

reabsorption

movement of filtered molecules from filtrate back into blood

active and passive process

active secretion

secretion of molecules from blood into filtrate

active process

factors that affect Cl_R

extent of protein binding

filtrate flow

health of kidney

presence of other drugs

pH of urine (can be alkalinized or acidified)

competitive inhibition of renal transport

decrease in elimination rate (competes for secretion)

increase in elimination rate (inhibits reabsorption)

adverse drug reactions

bioavailable fraction

fraction absorbed x fraction escaping first pass

f(1-E)

dose

(Target concentration x V_d )/ F

organ clearance

Q ( (C_in - C_out) / C_in )