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2060B: Pharmacology > Module 3: Distribution > Flashcards

Module 3: Distribution Flashcards

1
Q

Drugs distribute into compartments in the body where they may be (4):

A

1) stored
2) metabolized
3) excreted
4) exert their pharmacological effect.

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2
Q

The body’s compartments include

A
  1. Interstitial Space
    – The extracellular fluid that surrounds cells. Low molecular weight, water soluble drugs distribute in the interstitial space.
  2. Total body water
    – Includes the fluid in the interstitial space, intracellular fluid and the plasma.
  3. Plasma
    – The non-cell containing component of blood. Drugs strongly bound to plasma protein and high molecular weight drugs typically distribute in plasma.
  4. Adipose Tissue
    – The body’s fat. Lipid soluble (lipophilic) drugs distribute into adipose tissue.
  5. Muscle
    – Some drugs bind tightly to muscle tissue.
  6. Bone
    – Some drugs adsorb onto the crystal surface of bone with eventual incorporation into the crystal lattice. Bone can be a reservoir for the slow release of some drugs.
  7. Other tissues
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3
Q

What is drug distribution determined by? (3)

A
  1. Blood flow to tissues.
  2. Ability of drug to move out of capillaries.
  3. Ability of drug to move into cells.
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4
Q

The more drug that distributes out of the blood….

A

… the lower the concentration of drug in the blood.

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5
Q

How does blood flow to tissues affect distribution?

- I.e. Well perfused tissues vs. lower blood flow

A

1) In well perfused tissues such as the liver, kidney and brain, drug distribution is rapid.
2) Distribution to tissues with lower blood flow such as skin, fat and bone is much slower.

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6
Q

Poor blood flow rarely limits drug distribution in adult patients however some exceptions do exist…
- What are the exceptions? (3)

A

1) Patients with heart failure or shock may have reduced blood flow and therefore altered drug distribution.
- Ex. Traumatic accident

2) Solid tumours have low regional blood flow.
- The outer portion of tumours has a high blood flow, but the blood flow progressively decreases towards the middle.
- Therefore, it is difficult to attain high drug concentrations within solid tumours.

3) Abscesses (infection filled with pus) have no blood supply and are therefore difficult to treat with antibiotics.
- They are often drained prior to drug therapy

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7
Q

What is true about neonates blood distribution?

A

Neonates have limited blow flow and therefore may have limited drug distribution.

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8
Q

How do drugs move out of capillaries?

A

With the exception of the brain, drug movement out of the capillaries into the interstitial space occurs rapidly due to the permeable nature of the capillary wall
- Drugs move out of the capillary through fenestrations, gaps in the endothelial cells

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9
Q

How do drugs move into cells?

A

Once drugs leave the vasculature they must enter their target organ/cells to have an effect.

  • The cell membrane is a significant barrier to drugs reaching their targets.
  • In order for drugs to enter cells they must be sufficiently lipophilic to cross the cell membrane or be carried by an uptake transporter into the cell.

Some drugs are extruded (removed) from cells by efflux transporters.

  • Pump drugs from inside the cell to outside the cell
  • Limits cellular penetration of drugs
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10
Q

What is P-glycoprotein?

A

P-glycoprotein is the most widely studied efflux transporter and plays an important role in the distribution of drugs

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11
Q

Although the “P” in P-gp stands for permeability, it is helpful to remember the word “Protective” when you think of P-gp.

Why?

A

P-gp is protective because it facilitates drug efflux from cells, promotes drug excretion and protects the body from exposure to drugs and other toxins

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12
Q

What type of a transporter is P-glycoprotein?

A

P-glycoprotein is an active transporter which means that it requires energy (ATP) in order to transport drugs against a concentration gradient
- High to low concentrations

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13
Q

How is P-gp expressed in the liver?

  • Localized?
  • Function?
  • Result?
A

As Hepatocytes

  • Localized to the bile canalicular membrane of the liver
  • Functions to pump drugs from hepatocytes into the bile
  • Result – Drugs that are substrates for P-gp will be excreted in the bile
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14
Q

How is P-gp expressed in the intestine?

  • Localized?
  • Function?
  • Result?
A

P-gp is expressed as enterocytes (cells of intestine)

  • P-gp expressed on same side of lumen
  • Pumps drugs from inside enterocytes out into the lumen of the gut
  • Thus preventing absorption of drugs into the blood
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15
Q

How is P-gp expressed in the kidney?

  • Function?
  • Result?
A

P-gp expressed at apical membrane of the proximal tubule cells

  • Functions to excrete drugs into lumen of nephron of the kidney
  • Results in drugs being excreted into lumen
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16
Q

How is P-gb expressed in the brain?

  • Why?
  • Function?
A

P-gp expressed in the capillary endothelial cells

  • The brain is important organ and we want to limit exposure to toxins
  • Functions to pump toxins out of brain and back into the blood
17
Q

What are the two forms that drugs can exist in blood?

- Which can elicit a response?

A

1) Free unbound form
- Only free drug is available to elicit a pharmacological response

2) Bound to plasma proteins
- Proteins are large and therefore drugs that are bound to plasma proteins are unable to pass through capillary fenestrations

18
Q

What are the two major plasma proteins that bind drugs in plasma?
- What does each one have an affinity for?

A
  1. Albumin
    – Has a high affinity for lipophilic and anionic (i.e. weakly acidic) drugs
    - Albumin is responsible for the majority of protein binding.
  2. Alpha 1 acid glycoprotein
    – Binds primarily cationic (i.e. weakly basic) and very hydrophilic drugs
19
Q

Is plasma protein binding reversible?

- How?

A

Yes

If some of the free drug is removed (i.e. by the kidney), some of the protein bound drug will dissociate from the protein and become free
- Cycle continues

20
Q

What are conditions that affect plasma protein binding?What is the result?

1) Albumin
2) Alpha-1 Acidic Glycoprotein

A

1) Albumin
- Malnutrition, trauma, aging, liver and kidney disease cause a decrease plasma albumin concentration
- Results in an increase in free drug concentration which may result in toxicity (i.e. less albumin in their blood and therefore a higher free concentration of drug)

2) Alpha-1 Acidic Glycoprotein
- Aging, trauma and hepatic inflammation (i.e. in hepatitis) cause increased alpha 1 acidic glycoprotein concentration
- Results in decreased free drug concentration which may lead to ineffective therapy (i.e. more alpha 1 acidic glycoprotein in their blood and therefore a lower free drug concentration.

21
Q

What does the volume of distribution represent?

A

Represents the APPARENT volume that a drug distributes into:

Vd is the ratio of the total amount of drug in the body (D) to the plasma concentration of the drug (C), therefore:

Vd = D/C

22
Q

What is important to note about volume distribution (Vd)?

A

It is important to note that Vd is NOT a physical, anatomical space

Rather it is a calculated volume that helps determine the relative distribution of a drug within the body.

23
Q

What is a difficult concept of volume distribution?

A

Some drugs have a Vd much larger than the volume of the body due to extensive binding to tissue

24
Q

To understand Vd, review the fluid compartments of the body (3)
- The average 70kg person is how much fluid? How does this relate to the fluid compartments you stated above?

A

1) Plasma – The liquid (non-cell) portion of blood.
2) Interstitial Fluid – The fluid that surround the cells of the body.
3) Intracellular Fluid – The fluid inside cells.

The average 70kg person is 42L of water

  • Plasma = 4L
  • InterF = 10L
  • IntraF = 28L
25
Q

Characteristics of drugs with Small Vd (2):

- Can they leave the vascular space? Why or why not?

A

1) Highly protein bound (retained in plasma)
2) Large molecular weight (unable to pass through
capillary fenestrations)

These drugs are unable to leave the vascular space (plasma)
- Therefore these drugs tend to distribute into the plasma volume which is approximately 0.057 L/kg (or ~ 4 L in a 70 kg person).

26
Q

Characteristics of drugs with Intermediate Vd (3):

- Can they leave the vascular space? Why or why not?

A

1) Low molecular weight (able to pass through capillary fenestrations).
2) Very hydrophilic (can’t cross cell membranes).
3) Intermediate protein binding.

These drugs are able to leave the vascular space and enter the interstitial space however they are unable to enter cells.

  • Therefore these drugs tend to distribute into the extracellular fluid (plasma + interstitial space).
  • The extracellular space is ~ 0.2 L/kg (~ 14 L in a 70 kg person).
27
Q

Characteristics of drugs with Large Vd (3):

- Can they leave the vascular space? Why or why not?

A

1) Low molecular weight (able to pass through capillary fenestrations).
2) Lipophilic (able to cross cell membranes).
3) Minimal protein binding.

These drugs are able to leave the vascular space and the interstitial space.

  • Therefore these drugs tend to distribute into body compartments such as fat, bone, muscle and other tissues.
  • Drugs with a large Vd typically distribute into greater than 0.2 L/kg.
28
Q

Keep in mind that these drugs may have a Vd larger than total body water! How is this possible?

A

Remember that Vd is mathematically derived and is NOT an actual physical volume.

29
Q

How does drug displacement from protein occur?

  • Example?
  • Fate of the displaced drug?
A

Drug binding to protein is reversible.

  • If two drugs are present in the blood, one drug may displace the other drug from plasma protein.
  • The fate of the displaced drug depends on its volume of distribution
30
Q

Drug displacement:

Small vs. large Vd

A

If a small Vd:

  • When the Vd of the displaced drug is small, displaced drug does NOT distribute into tissues, it stays in the plasma
  • This means the free drug concentration increases.

If a large Vd:

  • When the Vd of the displaced drug is large, displaced drug leaves the plasma and distributes into the tissues
  • This causes the total plasma drug concentration to decrease, and the apparent Vd to increase even further
31
Q

As we age our body composition changes. How does this affect drug distribution (large vs. small Vd)?

  • Elderly people
  • Obesity
  • With age
A

Elderly people have an increased proportion of body mass as fat.

Similarly, obese people have a larger proportion of body mass as fat.
- Drugs that distribute in fat will have a larger Vd in obese or elderly people than young healthy adults.

As people age, they have a decreased percentage of muscle per total body mass.
- Therefore drugs that distribute into muscle will have a lower Vd.

2060B: Pharmacology (18 decks)

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