[LADME] Distribution

Proverbs 16:3

Distribution

This refers to the reversible transfer of a drug from the systemic circulation to the site of action (peripheral) and to the other compartments.

circulatory system

Drugs distribution throughout the body occurs primarily via the _____ system, which consists of a series of blood vessels that carry the drug in the blood; these include the arteries that carry blood to tissues, and the veins that return the blood back to the heart.

5 L of blood

An average subject (70kg) has about ____ L of blood, which is equivalent to about 3 L of plasma.

3 L of plasma

An average subject (70kg) has about 5 L of blood, which is equivalent to about ____ L of plasma.

60 % of Total Body Weight

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Total Body Water

35-40 %

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Intracellular fluid

20-25 %

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Extracellular fluid

● Interstitial fluid - 14 %

● Plasma - 5 %

● Transcellular - 1 %

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Extracellular fluid is composed of _____ [3]

Whole Body Fluid

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

This is typically measured using the volume of distribution of non-electrolyte substances that mix evenly with body water without binding or being metabolized.

● Thiosulfate

● Mannitol

● Inulin

→Mnemonic: “TMI”

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Chemical indicators used to measure EXTRACELLULAR FLUID [3]

• Trypan Red

• 131 I‑albumin (iodine)

• Tetraiodine fluorescein

• Evans Blue

→Mnemonic: “TITE”

[DIFFERENT BIOLOGICAL FLUID COMPARTMENTS]

Chemical indicators used to measure PLASMA VOLUME [4]

Diffusion- or Permeability-Limited Distribution

[RATE LIMITING STEPS ]

This occurs when a drug is limited by the slow diffusion across the membrane in the tissue.

Diffusion- or Permeability-Limited Distribution

[RATE LIMITING STEPS ]

• This is important particularly in the diameter of blood vessels.

  • Capillaries are the smallest blood vessel.

  • Blood Brain Barrier has tight junctions; not all drugs are able to permeate.

Perfusion- or Flow-Limited Distribution

[RATE LIMITING STEPS ]

This occurs when a drug crosses membranes very rapidly, so the blood flow to the tissue becomes the limiting factor.

● Lungs

● Heart

● Liver

● Kidney

[RATE LIMITING STEPS ]

Highly perfused organs include ____ [4]

● Skin

● Bones

[RATE LIMITING STEPS ]

Poorly perfused organs include ______ [2]

● Cardiac Output

● Regional Blood Flow

● Capillary Permeability

→Mnemonic: “CRC”

[FACTORS AFFECTING DRUG DISTRIBUTION]

Factors affecting drug distribution include _____ [3]

Cardiac Output

[FACTORS AFFECTING DRUG DISTRIBUTION]

This refers to the volume of blood pumped by the heart per minute, which is directly related to the extent of distribution.

2.2-3.5 L/min/sqm

[FACTORS AFFECTING DRUG DISTRIBUTION]

The normal cardiac output is _____ L/min/sqm.

TRUE

[FACTORS AFFECTING DRUG DISTRIBUTION]

TRUE OR FALSE:

• In patients with heart failure, reduced cardiac output and lower ejection fraction slow blood flow, which can reduce drug distribution to tissues.

  • This may lead to higher plasma concentrations and increased risk of toxicity, which is why dose adjustments are often necessary.

Regional Blood Flow

[FACTORS AFFECTING DRUG DISTRIBUTION]

This refers to the fraction of the cardiac output that reaches a specific organ or tissue.

Lungs

[FACTORS AFFECTING DRUG DISTRIBUTION]

Regional blood flow: 100%

● Liver

● Kidneys

[FACTORS AFFECTING DRUG DISTRIBUTION]

Regional blood flow: 25%

bones and adipose tissue (poorly perfused organs)

[FACTORS AFFECTING DRUG DISTRIBUTION]

Regional blood flow: < 1 %

Blood-Brain Barrier (BBB)

[FACTORS AFFECTING DRUG DISTRIBUTION]

Capillary Permeability:

• _____- has tight junctions, allowing limited entry.

Liver Lobules

[FACTORS AFFECTING DRUG DISTRIBUTION]

Capillary Permeability:

______- are discontinuous, spaces are present, which means all can enter.

● Volume of Distribution (Vd)

● Protein binding

[PARAMETERS IN DISTRIBUTION]

Parameters in distribution include _____ [2]

Volume of Distribution (Vd)

[PARAMETERS IN DISTRIBUTION]

It is the hypothetical value of body fluid required to dissolve a given amount of drug to a concentration equal to that of plasma concentration.

Volume of Distribution (Vd)

[PARAMETERS IN DISTRIBUTION]

It is the concentration of drug in the plasma or tissues, which depends on the amount of drug systemically absorbed and the volume in which the drug is distributed.

Vd = Xo / Cp

Where:

● Xo = amount of drug

● Cp = plasma concentration

📌 Unit: Liter (L) or any unit of volume

[PARAMETERS IN DISTRIBUTION]

Formula for Volume of Distribution (Vd):

● To estimate the Loading dose

● To estimate the actual distribution of drugs in the body.

[PARAMETERS IN DISTRIBUTION]

Applications of Volume of Distribution (Vd) [2]

4 - 5 half-lives

[PARAMETERS IN DISTRIBUTION]

How many half-lives are required to reach the steady state concentration?

Deep tissues

[PARAMETERS IN DISTRIBUTION]

Higher volume of distribution (Vd) means the drug has higher distribution in ____________.

Plasma (circulatory system)

[PARAMETERS IN DISTRIBUTION]

Lower volume of distribution (Vd) means the drug has higher distribution in ____________.

bones

Random BEQ:

Cadmium causes Itai-Itai disease, which primarily affects the _______?

TRUE

[PARAMETERS IN DISTRIBUTION]

TRUE OR FALSE:

As volume of distribution INCREASES, half-life also INCREASES.

TRUE

[PARAMETERS IN DISTRIBUTION]

TRUE OR FALSE:

As volume of distribution INCREASES, clearance DECREASES.

Protein binding

[PARAMETERS IN DISTRIBUTION]

A phenomenon which occurs when a drug combines with plasma protein or tissue to form a reversible complex

Albumin

[PARAMETERS IN DISTRIBUTION]

This plasma protein binds to weak ACIDIC drugs.

Alpha 1-acid Glycoprotein (AAG)

[PARAMETERS IN DISTRIBUTION]

This plasma protein binds to weak BASIC drugs.

Globulins

[PARAMETERS IN DISTRIBUTION]

This plasma protein binds to endogenous and exogenous substances, often including some HORMONES and DRUGS

● Longer duration of action (ADVANTAGE)

● Limit access to certain body compartments.

● Altered by other drugs as a result of drug competition resulting to Drug Displacement. (DISADVANTAGE)

[PARAMETERS IN DISTRIBUTION]

Consequences of Protein Binding [3]

TRUE

[PARAMETERS IN DISTRIBUTION]

TRUE OR FALSE:

Bound drugs are INACTIVE, which decrease the volume of distribution.

NSAIDs

[PLASMA PROTEIN BINDING]

These are very highly protein bound with 99%.

Phenylbutazone

[PLASMA PROTEIN BINDING]

This NSAID has VERY LOW volume distribution.

TRUE

[PLASMA PROTEIN BINDING]

TRUE OR FALSE:

Sulfa Drugs are also highly protein bound.

Digoxin + Quinidine

[PLASMA PROTEIN BINDING]

These drugs are more bound to ALBUMIN.

Quinidine can displace digoxin from its albumin-binding sites, increasing the free (unbound) fraction of digoxin in the plasma.

• This increase in unbound drug enhances pharmacologic effects and can lead to toxicity.

[PLASMA PROTEIN BINDING]

What will happen if Digoxin + Quinidine?