Drug Distribution

Question 1

What is drug distribution in the context of the cardiovascular system?

Answer 1

Drug distribution is the process by which a drug moves from the systemic circulation into different body tissues (target cells). After absorption, the drug is carried through the circulatory system, moving from blood vessels (intravascular space) to body tissues (extravascular space).

Question 2

What are the three layers of the heart wall?

Answer 2

The three layers of the heart wall are:

Endocardium: A single layer of endothelial cells.
Myocardium: The muscle layer, composed of cardiomyocytes.
Epicardium: Composed of mesothelial cells, fats, and connective tissue. The coronary arteries, veins, lymphatic vessels, and nerves run under the epicardium.

Question 3

What are the two main circulations in the cardiovascular system?

Answer 3

The two main circulations are:

Pulmonary Circulation: Transports blood from the right ventricle to the lungs and back to the left atrium.
Systemic Circulation: Carries blood from the left ventricle to tissues throughout the body and returns it to the right atrium.

Question 4

What are the three types of blood vessels and their functions?

Answer 4

The three types of blood vessels are:

Arteries: Carry blood away from the heart.
Veins: Carry blood toward the heart.
Capillaries: Tiny vessels that interconnect the smallest arteries and veins, facilitating exchange of gases, nutrients, and waste products.

Question 5

What are the three layers of blood vessel walls, and what is their function?

Answer 5

The three layers of blood vessel walls are:

Tunica Intima: The innermost layer consisting of endothelium, which regulates vascular permeability.
Tunica Media: The middle layer of smooth muscle, responsible for vasoconstriction and vasodilation.
Tunica Externa (Adventitia): The outer layer of connective tissue, providing support and anchoring the vessel to surrounding tissues.

Question 6

How is body fluid distributed in the body?

Answer 6

Body fluids make up about 60% of total body mass and consist primarily of water, electrolytes, metabolites, and proteins. There are two main compartments:

Extracellular Fluid (ECF): Approximately 20% of body water, found outside the cells.
Intracellular Fluid (ICF): Approximately 40% of body water, contained within the cells.

Question 7

How does a drug distribute across different body compartments?

Answer 7

After administration, the drug is absorbed into the plasma, then:

Moves from plasma to interstitial fluids through capillary walls.
Moves from interstitial fluids to intracellular fluids across cell membranes.
Eventually, equilibrium is reached when concentrations in each compartment are equal, unless metabolism or excretion alters the drug concentration.

Question 8

What factors affect drug distribution in the body?

Answer 8

The key factors affecting drug distribution are:

Permeability of cell membranes: The capillary structure, drug physicochemical properties, and ionization at physiological pH.
Blood flow: Organs with higher blood flow (like the liver and kidneys) receive more drug.
Drug binding: Plasma protein and tissue binding can affect the drug’s availability to tissues.

Question 9

How does capillary permeability affect drug distribution in septic shock?

Answer 9

In septic shock, capillary permeability is increased (capillary leak syndrome), leading to greater drug distribution but requiring higher doses to achieve effective concentrations at the site of action. Drugs with low lipophilicity may reach sites that are normally inaccessible, such as the central nervous system, but may require special administration routes (e.g., intrathecal for aminoglycosides).

Question 10

What properties of a drug affect its distribution across the body?

Answer 10

A drug’s distribution is influenced by its:

Molecular size: Smaller molecules distribute more rapidly.
Lipophilicity (fat-solubility): Non-polar drugs diffuse across cell membranes more easily.
Ionization: Unionized drugs are lipid-soluble and can diffuse across membranes more readily. For example, warfarin becomes more ionized at higher pH, reducing its ability to cross membranes.

Question 11

What is tissue protein binding, and how does it affect drug distribution?

Answer 11

Tissue protein binding occurs when drugs accumulate in specific organs or tissues, leading to higher concentrations in those areas compared to blood. This can prolong the drug’s action or cause local toxicity. For example, tetracycline accumulates in bones and teeth, causing discoloration, while amiodarone accumulates in the thyroid, potentially leading to toxicity.

Question 12

How does drug binding to plasma proteins affect drug distribution?

Answer 12

When a drug binds to plasma proteins, it becomes unable to diffuse out of the circulatory system to the site of action. Only the free (unbound) drug is available to reach tissues and exert its therapeutic effects. Higher protein binding can limit the distribution of the drug to target tissues and decrease its effectiveness.

Question 13

What is the role of the extracellular fluid (ECF) in drug distribution?

Answer 13

The extracellular fluid (ECF), which makes up approximately 20% of the body’s water, plays a crucial role in drug distribution by serving as the environment in which drugs first move out of the plasma and into tissues. The drug moves from the plasma to the interstitial fluids through capillary walls, and eventually to the intracellular fluid compartment to reach its target site.

Question 14

How does blood flow affect drug distribution in various tissues?

Answer 14

Blood flow significantly affects drug distribution because tissues with higher blood flow (such as the liver, heart, and kidneys) receive a greater supply of the drug and are more likely to be exposed to therapeutic concentrations. Conversely, tissues with lower blood flow (such as adipose tissue) may receive relatively lower drug concentrations, influencing the drug’s effectiveness in those areas.

Question 15

What are the implications of altered drug distribution during shock?

Answer 15

During shock, blood flow to various organs is reduced, leading to decreased drug delivery to tissues. This can result in lower therapeutic concentrations of drugs in critical organs, potentially reducing the effectiveness of treatment. For example, in shock, the body prioritizes blood flow to vital organs, and drugs may not reach their target tissues as efficiently, requiring careful adjustment of drug doses.

Question 16

What are microsomal mixed-function oxidases, and which family is most important in phase 1 metabolism?

Answer 16

Microsomal mixed-function oxidases are a group of enzymes involved in phase 1 metabolism. The most important of these enzymes are members of the cytochrome P450 family. These enzymes require the oxidase substrates NADH, NADH-P450 reductase, and molecular oxygen to carry out their function, which typically involves the oxidation of drugs to generate reactive derivatives.

Question 17

How does rifampicin affect warfarin concentration?

Answer 17

Rifampicin, an antibiotic, induces the enzyme CYP2C9, a member of the cytochrome P450 family. This induction increases the metabolism of warfarin, which may lower its concentration in the blood. As a result, patients taking both rifampicin and warfarin may require an adjusted dosage of warfarin to maintain its therapeutic effect.

Question 18

Why should grapefruit juice not be consumed with certain drugs?

Answer 18

Grapefruit juice contains compounds that inhibit cytochrome P450 enzymes, particularly CYP3A4, which is involved in the metabolism of many drugs. When grapefruit juice is consumed with certain medications, it can inhibit the enzyme activity, leading to higher drug concentrations in the blood, potentially causing adverse effects or toxicity.

Question 19

What is the role of phase 2 metabolism in drug metabolism?

Answer 19

Phase 2 metabolism involves the conjugation of a drug or its phase 1 metabolite with an endogenous substance, such as glucuronide, to form a more water-soluble compound. This conjugation typically increases the drug’s water solubility, making it easier to excrete through urine. The most common conjugation process is glucuronidation, which attaches glucuronide to atoms like nitrogen (N), oxygen (O), or sulphur (S) in the drug molecule.

Question 20

How does enzyme inhibition, such as with clopidogrel and omeprazole, affect drug metabolism?

Answer 20

Enzyme inhibition, like the interaction between clopidogrel and omeprazole, can slow down the metabolism of certain drugs. Clopidogrel, which requires CYP2C19 for activation, can have its metabolism reduced if omeprazole, a CYP2C19 inhibitor, is co-administered. This can lead to lower levels of the active metabolite of clopidogrel, reducing its effectiveness in treating conditions like vascular ischemia.