Drug Distribution - Dr. Sprowls

Once a drug is absorbed, what body compartment does it move into?

For drugs intended to be delivered systemically, a vast majority of these drugs will make their way into systemic circulation following absorption from the site of administration.

What kind of relationship occurs between drug dose and observed pharmacological effect?

A higher dose generally produced a greater effect.

What is a more precise relationship when it comes to drug distribution?

Concentration of drug in the plasma/ other bodily compartments (mg/mL) and an Observed Pharmacological Effect compared to the dose delivered (mg)

Measurements of a drug concentration at different time points in various tissues and the mathematical relationships that drive the change in concentration overtime in the body is the basis for the field of what? (How much when and where?)

Pharmacokinetics (PK)

The broader effect and relationship between the concentration of the drug at the intended site of action is referred to as? (How much does what?)

Pharmacodynamics (PD)

What is it called when you integrate PK and PD to optimize dosing, personally therapeutics, inform decision making, and predict drug outcomes.

PKPD

How do we measure the concentration of drugs and potential drug candidates?

By obtaining biological specimens

What are some of the most critical biological samples that help us understand what the body is doing to a drug following administration? (What is drug doing to the body?)

• Blood

• Urine

• Feces

• CSF

• Saliva

• Breath

• Tissues

What is the most sensitive, precise, and accurate analytical technique for detection of the drug in any biological sample?

Liquid Chromatography Tandem Mass Spec. (LC-MS)

• LC= separation of drug from biological

• MS= What is the drug and how much

What are the noninvasive methods of collecting samples for testing?

• Urine

• Feces

• Breath

What is the best sample method for gaining in site on drug action of effect?

Blood (main compartment for drug distribution)

What sample collection methods are considered invasive?

• CSF

• Tissue

• Synovial

When testing these samples, the amount of drugs in each of these biologic materials yields important information such as…?

• The amount of drugs retained in, transported into that region/fluid

• The likely pharmacologic or toxicological outcome of drug dosing and drug metabolite formation/transformation

Data collected from various biological specimens are always connected to a time of collection and are plotted against on another to form what kind of graph?

Plasma Concentration vs Time Profile

Following administration of drug, plasma drug concentrations will rise and fall reflective of what?

Absorption and Elimination

The difference that is observed at any point on the plasma concentration vs time plot is driven by the process…

Happening to the greatest extent

Where is the distribution phase on these types of plots? (Plasma lvl vs time)

The ENTIRE graph

As a drug is simultaneously undergoing all PK processes at once, eventually enough drug will accumulate into the plasma and subsequently be delivered to its sit of action that a _____ _______ _________ is reached

Minimum Effective Concentration

What does the minimum effective concentration refer to?

The smallest amount of drug required to elicit some pharmacological effect.

Drug can also accumulate to an extent that barely enough is present at the receptor that a toxic response can be observed. What is this concentration called?

Minimum toxic concentration or Maximum safe concentration

The intensity of a drugs effect is proportional to the # of receptor occupied by the drug. This is reflected by the clear relation of what?

Concentration and Response (not enough drug = no response)

The duration of a drugs action is the time between onset time need to reach MEC and the time once there required for plasma drug concentration to do what?

Fall back below MEC

What is the range of concentrations between the MEC and MTC called? What is another way to display this relationship, and what does this mean for drug development/safety?

Therapeutic Window

Therapeutic Index= LD50/ED50

Whole Blood is a complex heterogenous mixture of what?

Cells, Macromolecules, and H2O

The dynamic movement of drugs within whole blood is the first step of what?

Drug Distribution

As drug interacts with the constituents of whole blood during drug distribution phase, it will have marked influence on what?

On rate and extent of distribution (extend duration of pharmacological effect.

Drug bound to white blood cells, platelets and lipids is insignificant effect and can be IGNORED unless they are an important what? What is a good example?

Site of action (ex. Anticoagulants/thrombotics)

Drugs are capable of binding to any component of whole blood and is heavily influenced by the _______ _______ of that drug.

physiochemical properties

Binding is usually ____ (reversible/irreversiblle), nad drugs will move back and forth from being _______ &______

Reversible

Bound & Unbound

Drugs with requisite properties can bind to what? What drug is an example of this?

Red Blood Cells (RBCs)

(Ex. Doxorubicin)

What are the 4 Components of WHOLE BLOOD?

1. Plasma

2. RBCs

3. WBCs

4. Platelets

What percent of WHOLE BLOOD is plasma?

55%

What Percent of WHOLE BLOOD is RBCs?

45%

What percent of WHOLE BLOOD is WBCs & Platelets?

<1%

What are the 3 PLASMA components?

1. Water

2. Proteins

3. (Electrolytes, nutrients, lipids, dissolved gases, waste products like urea)

What percent of water is in PLASMA?

91%

What percent of Proteins is in PLASMA?

7%

What percent of Electrolytes, nutrients, lipids, dissolved gases, and waste products are in PLASMA?

<2%

Drugs moving within the blood are subject to binding to each component of whole blood. What two components are the majority?

RBCs & Protein

Movement of drug unbound from these elements into tissues is d=critical for what?

Drug distribution

Once drug is in the tissue, drug may bind to a non-specific sites that do not produce ___________ _____.

pharmacological effects

The transport process that allows the movement of free drug from the blood into the tissue is called? What is this described by?

Passive diffusion

Described by Fick’s Law of Diffusion

Another mechanism of drug penetration into tissue is caused by the pressure gradient between the arterial end of the capillaries entering the tissue and venous capillaries leaving the tissue called what?

Hydrostatic pressure

What type of drugs are driven into tissues by hydrostatic pressure?

Drugs that are:

• Hydrophilic

• High MW

• Monoclonal Antibodies

The fraction of drug bound to its target receptor is usually low relative to the amount of drug in a tissue that is free or bound to what type of binding sites?

Non-specific binding sites

Binding to a target receptor has a negligible impact on OVERALL Pharmacokinetics of a drug. The ONLY exception to this is in cases where a drug binds to its target with incredibly HIGH AFFINITY. This is called what?

Target Mediated Disposition

What is an example of target mediated disposition?

• Monoclonal Antibodies (low dose)

  • At high doses, clearance can be lowered

At equilibrium, the [ ] of unbound drug in the tissue will EQUAL the [ ] of unbound drug in the blood. Extensive binding of drug to NON-SPECIFIC sites in the tissue may result in the total concentration of drug being higher in the (tissue/blood)?

Tissue

In contrast to a scenario with exceedingly high tissue binding, a drug that is extensively plasma protein bound will result in most of the dose being in the _____.

Blood

What else could result in high concentrations of drug being limited to the blood?

• High Hydrophilicity

• High Polarity

• High MW

  • All these factors don’t allow them to cross cell membranes well

What does the Free Drug Hypothesis State? (MUST KNOW THIS)

ONLY Free Unbound Drug will/is capable of diffusing across biological membranes & interacting with its target.

Because of the free drug hypothesis, measuring what component is important when considering the overall pharmacokinetics of a drug?

Free Drug

When the [ ] of drug bound to protein is high, this may necessitate a higher dose may be needed to obtain the same intensity of drug effect than if the drug were what?

Completely free

Free drug concentrations are incredibly costly and challenging to measure, therefore, you can only commonly measure what instead?

Total Drug

The development of cost efficient approach to measure extent of protein binding IN VITRO has added an additional layer of rigor to traditional PK which is called?

Rapid Equilibrium Dialysis

When the unbound drug concentration in fresh blood perfusing a tissue is high, the CONCENTRATION GRADIENT between blood and tissue results in a net movement of drug into where?

Into Tissues

As drug is eliminated, the concentration of unbound drug DECREASES, and the concentration gradient between the blood and the tissue falls, causing the net movement of drug to move where?

From the tissue back into the blood

What does the dynamic equilibrium between blood and tissue concentration of free drug ensure?

It ensures that the drug does not remain at its target indefinitely.

An exception to the drug not remaining at its target indefinitely is the rare case of what? What drugs are examples of this?

Drugs irreversibly binding to its targets (PPIs & Aspirin)

Drugs that DO NOT distribute into tissues by means of passive diffusion across a concentration gradient move towards their target via what?

Blood flow mediated Drug DIstribution

The mass movement of fluids into and out of capillary beds is referred to what?

Bulk Fluid Flow

The force that drives fluid transport between the body’s capillaries and tissues is known as Hydrostatic Pressure. More specifically, the pressure exerted by the blood against the walls of the capillaries is called?

Capillary Hydrostatic Pressure

The process & movement of fluid out of capillaries and into the intercellular space is called what?

Filtration

The movement of fluid from capillary system into tissues causes a rise in the pressure of interstitial fluid also known as?

Interstitial Fluid Hydrostatic Pressure

The number in the Interstitial Fluid Hydrostatic Pressure is generally offset by the the continuous reabsorption of excess fluid by the what system?

Lymphatic System

What is the average Hydrostatic Pressure at the arteriole end of the capillaries?

32-36 mmHg

Because the pressure at the arteriole end of the capillaries is considerably higher than the pressure in the tissue, where does the net fluid flow go?

Into the tissues

What is the average capillary hydrostatic pressure in the VENULES?

12-17 mmHg (The difference in the pressure here at this point does NOT drive fluid movement back into the capillaries)

What is the pressure that drives fluid reabsorption?

Osmotic/Oncotic Pressure

Osmotic is different from hydrostatic pressure (driven by pressure exerted by fluid movement) because…..

It is driven by a concentration gradient with more specifically the CONCENTRATION IN SOLUTES.

In osmotic pressure, the region that is HIGHER in solute concentration than in water concentration will DRAW FLUID ACROSS a semi-permeable membrane from a region in which the water concentration is (higher/lower)?

HIGHER

Do formed elements of the blood contribute to osmotic concentration? If so, which ones?

NO, they do not contribute

Do elements of plasma contribute to osmotic pressure? If so which ones?

YES, plasma proteins contribute

Why are plasma proteins able to contribute to osmotic pressure?

Unlike solutes, plasma proteins DO NOT DISSOLVE, and are rather DISPERSED/SUSPENDED in their fluid medium creating a Colloidal Fluid System

What is the pressure created by the colloidal proteins in the plasma, which is responsible for fluid reabsorption into capillaries called?

Blood Colloidal Oncotic Pressure

Why is BCOP always higher than IFCOP?

large proteins like albumin stay trapped inside the Blood Vessels while remaining nearly absent in the interstitial fluid.

Because BCOP is higher than IFCOP, fluid will be….

Out of the tissues or into the capillaries

The pressure exerted on the walls of the capillaries are HIGH when blood is making it way to the capillary bed. What is this pressure?

35 mmHg

This pressure gradually Decreases as blood moves towards the venule end of a capillary. What is the pressure towards the venule end?

18 mmHg (This pressure is nearly always higher than the pressure in the tissue, so fluid will be pushed into the tissue)

What would happen to total fluid if not for BCOP?

There would be continuous buildup of fluid outside capillaries.

What pressure is BCOP throughout the length of a capillary and is the driving force for reabsorption of fluid that would otherwise be lost?

25 mmHg

What is the difference between hydrostatic pressure and BCOP? ANd what kind of movement does it drive?

Net Filtration Pressure (NFP)

• This drives FLUID movement

Where does fluid move when NFP is HIGH?

Into the tissue

Where does fluid move when NFP is LOW?

Fluid movement is out of tissues AND reabsorbed into the venules.

Does NFP have to be positive or negative in the VENULES of capillaries?

NEGATIVE

Tissue profusion refers to the process of delivering what to tissues and organs, ensuring each receives adequate oxygen, nutrients, and other essential molecules, while also carrying AWAY waste products.

Delivering Blood

Tissue Profusion can VARY GREATLY from tissue to tissue in the bosy, and is driven by their relative what?

Functionality (Ex. Kidneys vs Liver vs Skin)

The rate of perfusion (blood flow) to a particular organ can have a dramatic impact on what of what of a drug in various tissues following administration?

Distribution

The rate limiting step for many lipophilic drugs into any specific tissue is the what to that tissue?

Tissue Perfusion rate

What is an example of how tissue perfusion rate is a rate limiting step for a lipophilic drug?

In experiments measuring BBB permiability for various neurotheraputics like DIAZEPAM (MW= 284, LogP = 3; Kin = 2.43 mL/min/g) is used as a marker for cerebral blood flow. drugs that follow this are said to have Perfusion Limited Distribution.

What kind of limitation do drugs with Low LogP values, are Water soluble, polar, or those with high MW (ex. acyclovir, MW = 225, LogP = -1.3) have?

Permeability Limited

What drug is an example of systemic Distribution rate-limited by REGIONAL PERFUSION?

Thiopental

What was Thiopental Historically used for?

Induce unconsciousness/anesthesia prior to surgery

What kind of onset of action and duration of action did Thiopental have? (MW=264, LogP=1.9)

RAPID Onest of action &

SHORT duration of action

Thiopental has a RAPID decline in plasma concentration not because of metabolism/elimination, but rather because of what?

IMMEDIATE and Rapid DIstribution rates to tissues with High Perfusion Rates (Brain)

As Thiopental reaches peak concentration in the brain, what is happening when it starts descending?

Equilibrium between Blood and brain is reached, and dw/dt=PAC favors movement of drug into blood

Why does thiopental distribute more slowly to lean tissues and Fat?

They are areas of the slowest profusion rates

Thiopental is an example of how timing of the peak plasma concentrations does NOT always predict the peak of what?

Pharmacological Effect

Which pharmacokinetic model is right to describe a given drug distrubution process?

Depends on the distribution to which tissues and how many compartments there are

Which pharmacokinetic model will accurately predict a drug where Distribution into ALL tissues is achieved rapidly and equally?

One-Compartment Model