4 - Pharmacokinetics

Question 1

What does ADME stand for?

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

What methods of drug administration are there?

Answer 2

Oral - ingestion, inhalation, (buccal [cheek], sublingual [tongue])
Dermal
Subcutaneous
Intramuscular
Intraperitoneal
Intravenous

A depot injection is an injection, usually subcutaneous, intradermal, or intramuscular, that deposits a drug in a localized mass, called a depot, from which it is gradually absorbed by surrounding tissue. Such injection allows the active compound to be released in a consistent way over a long period.

Question 3

What determines the method of administration?

Answer 3

Whether the desired effect is systemic or local.
The route of administration is a critical determinant of the onset, duration, intensity and degree of localisation of drug action.

Question 4

What do enteral and parenteral mean?

Answer 4

Enteral means via the GI tract - sublingual, buccal, oral, rectal

Parenteral means all other methods - intravenous, intramuscular (DEPOT THERAPY), subcutaneous, percutaneous, inhalation

Question 5

What are the two main ways drugs move around the body?

Answer 5

1. Bulk flow transfer i.e. bloodstream

2. Diffusional transfer i.e. short distance

Question 6

Drugs cross both liquid and aqueous environments. Where are these environments found?

Answer 6

Liquid compartments - blood, lymph, EC/IC fluid

Lipid barriers - cell membranes

Question 7

How do drugs cross barriers?

Answer 7

1. Passive diffusion (lipid soluble) - pH PARTITION HYPOTHESIS
2. Across aqueous pores/facilitated diffusion (least common as pores and therefore drug must be very small <0.5nm)
3. Carrier proteins/active transport (water soluble)
4. Pinocytosis (rare) - via liposomes
5. Filtration (small water soluble molecules)
6. Paracellular transport (around cells, often overlooked).

Question 8

How many membranes does the average membrane have to cross in the body?

Answer 8

3, if orally ingested and the target is on the cell surface.

From the small intestine - capillary wall (in) - capillary wall (out) to EC fluid - drug target

Question 9

What are most drugs which affects their ability to travel freely?

Answer 9

Either weak acids or bases which are either ionised or unionised depending on the local pH.

Question 10

What is aspirin at physiological pH?

Answer 10

Weak acid

Question 11

What is morphine at physiological pH?

Answer 11

Weak base

Question 12

What is pKa?

Answer 12

The dissociation constant

N.B. It is CONSTANT, only pH and concentrations change.

Question 13

Apply the pH partition hypothesis/Henderson-Hasselbalch equation to a weak base.

Answer 13

10^(pKa-pH) = [BH+]/[B]

Question 14

Apply the pH partition hypothesis/Henderson-Hasselbalch equation to a weak acid.

Answer 14

10^(pKa-pH) = [AH]/[A-]

Question 15

What is ‘ion trapping’?

Answer 15

Drugs can get localised within certain compartments. This changes the proportion of drug that will reach the target.

e.g. Aspirin diffuses easily out of the GI tract but it is more difficult for it to diffuse out of the blood

Question 16

Give an example where ‘ion trapping’ trapping can be manipulated

Answer 16

Treatment with IV sodium carbonate increases the pH of urine and ionises a greater proportion of aspirin. This increases the rate of excretion. This is a common method used for acidic drugs e.g. overdose.

Question 17

What factors influence drug distribution?

Answer 17

1. Regional blood flow
2. Extracellular binding (plasma proteins)
3. Capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental)
4. Localisation in tissues

Question 18

What is the distribution of blood to different organs?

Answer 18

At rest:
Liver 27%
Kidneys 22%
Brain 14%
Heart 4%

Muscle 20% (during exercise)

Question 19

What are the clinical implications of plasma protein binding?

Answer 19

If plasma protein bound, the drug cannot leave the bloodstream, reducing the amount which can reach the target e.g. warfarin 90%, aspirin 50-80%. This is especially a problem with acidic drugs.

In addition, if drugs are coadministered, they can displace each other from plasma proteins which can increase the amount reaching the target.

Question 20

What are the types of capillary permeability?

Answer 20

Continuous - H20 gap filled junctions
Blood brain barrier - Tight junction
Fenestrated
Discontinuous

Question 21

What are the clinical implications of tissue localisation for drug distribution?

Answer 21

If drugs are very fat soluble e.g. general anaesthetics

75% may be partitioned in adipose tissue and can be subsequently released.

Question 22

What are the two major routes of drug excretion?

Answer 22

1. The kidney
2. The liver - via concentration into bile (v. large molecular weight conjugates)

+ Lungs – excreted via expired air, passive diffusion of volatile compounds

Other routes (usually of little quantitative importance) = gastrointestinal secretions, saliva, sweat, milk, genital secretions, integument.

Question 23

Outline the process of drug excretion at the kidneys

Answer 23

20% of the blood is ultrafiltrated at the glomerulus, 80% passes by.
Only low molecular weight drugs can pass through here.

At the kidney and proximal tubules, basic and acidic drugs are actively secreted into the lumen dependent on available transporters.

Lipid soluble drugs will return to the bloodstream at the distal convoluted tubule and collecting duct.

N.B. This is why the goal of metabolism is to make drugs more water soluble.

Question 24

Outline the process of drug excretion in the liver

Answer 24

There is a discontinuous structure in the liver, allows easy access to hepatocytes.

However water soluble metabolite produced by hepatocytes cannot get into the bile duct from the blood, requires an active transport system.

Question 25

What is the ‘enterohepatic cycling’?

Answer 25

The water soluble metabolite is excreted via the bile into the gut where gut bacteria breaks down the conjugate, refreeing the free drug (cleaving the glucuronide conjugate).
The free drug is lipid soluble again and is reabsorbed into the intestinal capillaries and transported back to the liver via the hepatic portal vein.
At the liver the drug can also return to the systemic circulation.

This is known as ‘drug persistence’.

Question 26

What can you predict?

Answer 26

The time course of drug action

Question 27

What is bioavailability? (linked to absorption)

Answer 27

The proportion of administered drug that is available within the body to exert its pharmacological effect.

Measured via areas under concentration versus time curves.

Question 28

What is ‘apparent volume of distribution’? (linked to distribution)

Answer 28

The volume in which a drug appears to be distributed e.g. fat soluble drugs can occupy a larger apparent volume as they can also enter adipose tissue - an indicator of the pattern of drug distribution

Question 29

What is ‘biological half-life’? (linked to metabolism/excretion)

Answer 29

Time taken for the drug concentration to half (in blood).

Question 30

What is ‘plasma clearance’? (linked to excretion)

Answer 30

The volume of blood (plasma) cleared of a drug in a unit time. Sum of total processes if more than one.

Question 31

What is the therapeutic window?

Answer 31

The range of doses which can treat a disease effectively without having toxic effects.

Question 32

What is first-pass metabolism?

Answer 32

A phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. Mostly due to the liver and the gut wall.

Question 33

Mrs. Beryl is a 57-year-old with chronic hypertension and takes oral propranolol twice daily. Doctors recently found that her liver function tests have declined so immediately reduced the dosage of her medication. Which of the following is the best explanation for why her dosage was altered?

1. Propranolol causes cirrhosis of the liver over time
2. Absorption of propranolol increases in patients with liver failure
3. Liver failure reduces first pass metabolism of propranolol
4. Excretion of propranolol decreases in patients with liver failure
5. The distribution of propranolol changes in patients with liver failure

Answer 33

3. Liver failure reduces first pass metabolism of propranolol

Question 34

What is depot therapy?

Answer 34

A depot injection is an injection, usually subcutaneous, intradermal, or intramuscular, that deposits a drug in a localized mass, called a depot, from which it is gradually absorbed by surrounding tissue. Such injection allows the active compound to be released in a consistent way over a long period.

Question 35

Could the selective uptake of drugs into the lymphatic
system be used to any therapeutic advantage and, if so,
how could this be achieved?

Answer 35

The lymphatic route is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism.
The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system.

How would it be achieved?

Question 36

To what therapeutic advantage could enterohepatic cycling be put?

Answer 36

Increasing drug persistence and duration of action

Lower doses of drugs can be therapeutically effective because elimination is reduced by the ‘recycling’ of the drug.

N.B. For a small number of drugs that are very toxic to the intestine (e.g. irinotecan), these molecules which would not otherwise be very toxic can become so because of this process, and therefore inhibition of this step can be protective.