Exam 3: Drug distribution and TDM Flashcards
Therapeutic Drug Monitoring (TDM)
Using assays to measure drug concentration to develop safe and effective dosing regimens
- The aim is to maintain the plasma drug concentration within a therapeutic range
- safe and effective drugs
When to use Therapeutic Drug Monitoring
- Drugs with a narrow therapeutic range
- When the consequences to giving too much are
serious or irreversible - When the consequences to giving too little are
serious or irreversible - Strong correlation of plasma [drug] w/response
-Wide interpatient variability
-• Cannot assess response clinically such as BP, Respiratory rate
Drugs with narrow therapeutic range examples
Ex: • Phenytoin: 10-20 mcg/mL • Theophylline : 5-15 mcg/mL • Digoxin: 0.5-2 ng/mL • Tacrolimus: 5-20 mcg/L
Tacrolimus example of being given too little and too much
immunosuppressant in organ
transplant
- Too much: Acute renal failure
- Too little: Graft rejection
When not to use Therapeutic Drug Monitoring
- Wide therapeutic index
- No significant consequences to too low or too high levels
- Minimal patient to patient variability
- ## Weak correlation of [drug] w/response
Distribution
Ideally, we want the drug to reach the target sites rapidly with limited accumulation in non-target organs and at a concentration that is effective and non-toxic
- function of blood flow
What can impact drug distribution
Individual patient characteristics and disease states
Vascular space
Within blood vessels
• Intracellular (blood cells)
• Plasma
Extravascular space
Intracellular space
• Interstitial fluid
Most drugs are
selective’, not ‘specific’
Drugs bind to
to target receptors, but also can bind to non-target entities
Drugs may be distributed to organs that eliminate them
Liver- Metabolism
Kidneys-Excretion/ Elimination
Drugs can be distributed to other places as well such as
• into fat or saliva
• into breast milk and the placenta
- may have impact on developing fetus
How many liters of blood in body
Approximately 5 L of blood is in the adult human
body
The heart pumps the entire volume in ~1 minute
- Flow rate: ~5 L/min.
Certain organs recieve more of this blood flow than others such as
Liver, heart and kidney
What is the function of arteries
carry blood leaving the heart to the tissues
- carries blood away from heart
Process of blood from arteries to capillaries to tissues
- Arteries branch into small arterioles
- Small arterioles branch into capillaries
- Capillaries feed the interstitial fluid between cells
Q represents
blood flow
Perfusion-Limited Distribution
Uptake is limited by delivery, rather than passage
- Permeability (PA) across cellular or membrane barriers is much greater than blood flow (Q) to
that tissue
Distribution Processes and Blood Flow
In some disease states, blood flow is the limiting step for drug distribution
Hydrostatic pressure
Pressure gradient from the arterial end of the capillaries entering the tissue to the venous capillaries leaving the tissue
Filtration pressure
, fluid leaves the capillaries and enters the tissues
- This is bc there is an ~8 mm Hg greater pressure in the capillaries at the arterial end than the tissue
Absorptive pressure
fluid leaves the tissues and returns to the capillaries
-This is bc at the venous end, the pressure is ~8 mm lower than the tissue
Absorptive pressure
fluid leaves the tissues and returns to the capillaries
-This is bc at the venous end, the pressure is ~8 mm lower than the tissue
For efficient filtration of drugs into the urine,
a high arterial hydrostatic pressure must exist
Decreased blood flow due to congestive heart failure
may reduce renal clearance through reduced blood flow
A higher arterial hydrostatic pressure causes
fluid to leave the capillaries and enter the tissues
A lower hydrostatic pressure causes
fluid to leave the tissues and return to the capillaries
Permeability-Limited Distribution
Uptake is limited by permeation, rather than delivery Blood flow (Q) to that tissue is much greater than permeability across cellular or membrane barriers (PA)
Ex of Permeability-Limited Distribution
The brain gets plenty of blood flow, but restricted permeation
Blood-brain barrier (BBB) -tight junctions between glial cells as well as acting as a thicker lipid barrier
Distribution Processes and Blood Flow
Unless there is pressure, entry into an organ is based primarily on concentration-dependent diffusion
- Ficks law
In some disease states, permeability is altered which affects drug distribution
Inflammation and burns yield
increased permeability which may increase a drug’s ability to permeate tissues
Rate of distribution
Kd
- takes into account blood flow (Q), the volume of an organ (V), and the partitioning of the drug into the organ (R=ratio of drug concentration in the tissues to drug concentration in the blood)
Rate of distribution formula
• kd=Q/(VR)
The greater the blood flow
the faster the distribution
- Exercise increases blood flow and increases distribution
The larger the organ
the slower the distribution
- It will take longer to fill a larger organ with drug than a smaller organ
Distribution to Kidney is
fast
Distribution to skin, muscle and fat
are slow
R pertaining to distribution
ratio of drug concentration in the tissues to drug concentration in the blood
A high log P generally correlates with
- large R values in vivo
- There may be plenty of drug that reaches the kidney, liver, and lung, but little accumulation in
the brain
If a drug extensively partitions into the tissues, we would expect the volume of distribution to be
large
plasma drug conc. will be low because drug is in tissues
If a drug partitions extensively, we would expect it to have a (long/short) elimination half life
long
- it will take drug a long to get out of the body bc the plasma drug conc. is low
- Only drug in plasma can be cleared
If it takes a long time for a drug to partition into the tissue
it will take a long time for it to leave the tissue once the blood concentration decreases
Increased drug-lipid solubility and drug-protein binding yield
longer distribution half-lives
Drug uptake into a tissue depends on
partitioning and binding to specific components/receptors
• This is a reversible process
A drug that has weak affinity for the tissues will
re-equilibrate rapidly with the plasma
- Its plasma drug concentration will decline rapidly as it then is eliminated from the body
A drug that has high affinity for the tissues will
re-equilibrate slowly with the plasma
- Its prefers the tissue, hence plasma drug concentration will be low and elimination will be slow
Blood flow to the adipose tissue is
low
- It will take a long time for a drug to accumulate there, but once it does, it will take a long time for it to
be removed
OATP
Organic Anion Transporting Polypeptide
- influx
OCT
Organic Cation Transporters
- Influx and Efflux
movement of ions in cell vs out of cell
p-glycoprotein involved in
efflux
Efflux transporters
shunt drugs out of cells
Limits toxicity, but can impede therapy!
Not limited to GI tract!
Complexation and Protein binding
Drug molecules can complex with components which hinder absorption, distribution, metabolism,
or excretion
-In the gut, there may be complexation with: Multivalent ions
- Usually a reversible process
In certain tissues
there may be binding to certain proteins
In the blood, there may by binding to many constituents, including
RBCs
WBCs
Plasma proteins
Plasma Protein binding
Protein binding has marked effects on drug distribution, metabolism, and excretion
- Only the free drug passes biological membranes
Free drugs can
be metabolized or excreted by the kidneys!
- typically exerts a biological effect
Plasma and Extracellular Protein Binding
Drugs bound to plasma proteins are in an equilibrium with free drug
- The free drug can pass the capillaries to reach extracellular water and remain free, be in
complex with other proteins, or pass cellular membranes
Most drugs are
extensively protein bound
- The dose is adjusted to provide therapeutic effect
The extent of protein binding affects
the VD, Cl, t1/2
Fu
fraction of drug that is protein bound
If fu is high
, the drug is readily available for metabolism/distribution/excretion
If fu is low
not much of the drug is readily available for these processes
The total drug concentration of drug in the body (Cb) is a function
of its concentrations (C) and
volumes (V) in the plasma (p) as well as the tissues (t)
CB=Vp*Cp+VtCt
Drug protein bound. At steady state
there is an equilibrium between bound and unbound (u) drug in the plasma (p) and tissue (t)
Cup = Cut
If your drug has reversible binding
then the proteins act as a pool
- As it releases, it serves as a continual pool that can be metabolized and eliminated
If your drug binds tightly to proteins
then the proteins act as a sink
- Proteins accumulate the drug reducing its activity/clearance
The levels of plasma proteins can vary by condition/disease state
- May be suppressed or elevated
- Dehydration, bone marrow disorders, infections, inflammation
- Malabsorption of nutrients, kidney/liver disease, bowel disorders
- Certain proteins are elevated with certain disease states
A molecule that becomes more active after metabolism is a _____________.
• A. Drug
• B. Prodrug
• B. Prodrug
If enzymes are induced, metabolic activity for a drug will_____________.
• A. Increase
• B. Decrease
• A. Increase
If enzymes are induced, clearance for a drug will_____________.
• A. Increase
• B. Decrease
• A. Increase
If enzymes are induced, the hepatic extraction ratio will_____________.
• A. Increase
• B. Decrease
• A. Increase
The blood flow to the liver has decreased due to congestive heart failure, but the
liver’s metabolic capacity is unchanged. Your hepatic clearance
will_____________.
• A. Increase
• B. Decrease
• B. Decrease
An herbal supplement which competes for the same CYP450 as Drug A will cause
the plasma concentration to _____________.
• A. Increase
• B. Decrease
A. Increase
A patient drinks a glass of grapefruit juice while taking their daily dose of
phenytoin. The plasma concentration of phenytoin will likely _____________.
• A. Increase
• B. Decrease
• A. Increase
will stop metabolism of phenytoin which will cause more drug to accumulate in the plasma conc
A patient is taking an herbal supplement which competes for plasma proteins with
your drug. The hepatic clearance of your drug will_____________.
• A. Increase
• B. Decrease
• A. Increase
If drug is happily bound to plasma protein, it is protected so that it is not metabolized or excreted. But now the drug is displaced and is now feee
