[2] - Bioavailability

Question 1

What is a medicine?

Answer 1

Medicines are the dosage forms used, which contain the drug in question and also include a number of other materials called EXCIPIENTS.

Question 2

What are excipients?

Answer 2

These excipients may be added to aid the manufacture of the medicine, to improve its chemical and biological stability or to increase its acceptability to the patient by improving its flavour, fragrance or appearance.

Question 3

What is the process of developing a medicine called?

Answer 3

The process of making a medicine containing a drug is called FORMULATION and is an important part of the development process in the pharmaceutical industry.

Question 4

What are formulations?

Answer 4

A drug may be available in a number of different formulations that have been designed for use via different routes of administration. For example, a sterile solution of a drug in isotonic saline may be available for intravenous injection. The same drug also may be available in a pressurised aerosol formulation for (metered dose) inhalation, or as an ointment (or cream, lotion, paste) for application to the skin surface.

In addition, several different formulations may have been designed for use with the same route of administration. For example, liquids, syrups, tinctures, powders, soluble (effervescent) tablets, capsules, tablets and enteric-coated tablets all have been formulated for oral use. Each of these formulations may have their own particular advantages.

Question 5

What are the advantages of oral administration?

Answer 5

It permits self-medication

It does not require rigorously sterile preparations

The incidence of anaphylactic shock is lower (than intravenous)

There is the capacity to prevent complete absorption (vomiting, lavage).

Question 6

What are the disadvantages of oral administration?

Answer 6

It is inappropriate for drugs which:

• are labile in acid pH of stomach or otherwise degraded
• or undergo extensive ‘first-pass’ metabolism

It requires patient compliance.

Question 7

What are the advantages of intravenous administration?

Answer 7

rapid onset of action

avoids poor absorption from, and destruction within, the g.i. tract permits careful control of blood levels

Question 8

What are the disadvantages of intravenous administration?

Answer 8

slow injection necessary (to avoid toxic bolus) higher incidence of anaphylactic shock

trained personnel required

complications possible; embolism, phlebitis, pain

Question 9

What are the advantages of inhalation?

Answer 9

ideal for small molecules, particles, gases, volatile liquids, aerosols

enormous surface area presented by alveolar membranes

simple diffusion, also phagocytic cells clear particles

Question 10

What are the disadvantages of inhalation?

Answer 10

possible localised effect within lung (unless this is desired)

Question 11

What are the advantages of intramuscular administration? (into connective tissue reservoir in muscle block)

Answer 11

relatively high blood flow, increased during exercise enables DEPOT THERAPY (prolonged absorption from pellet, microcrystalline suspension or solution in oily vehicle).

Question 12

What are the disadvantages of intramuscular administration? (into connective tissue reservoir in muscle block)

Answer 12

possible infection and nerve damage (especially in gluteal region)

Question 13

What are the advantages of subcutaneous administration? (into connective tissue spaces under skin)

Answer 13

Local administration, dissemination can be minimised for local effect

enables DEPOT THERAPY (as for intramuscular)

Question 14

What are the disadvantages of subcutaneous administration? (into connective tissue spaces under skin)

Answer 14

pain, abscess, tissue necrosis

Question 15

What are the advantages of percutaneous administration?

Answer 15

local application and action

lipid soluble compounds diffuse rapidly (may be assisted by vehicles)

Question 16

What are the disadvantages of percutaneous administration?

Answer 16

local irritation and skin reactions

alteration of skin structure (e.g. steroids – subcutaneous adipose tissue)

Question 17

Does the formulation affect the drug?

Answer 17

Although it might be thought that the process of formulation would not influence the properties of the drug in the medicine, over the years many examples have been described which show that the action of drugs may indeed be determined by the nature of the excipients included with it. For example, in 1969, it was shown that the plasma levels and cardiovascular effects of digoxin varied greatly when patients were given tablets made by different companies in different ways, even though they all contained the same amount of drug. Since then, many cases of this phenomenon have emerged. To explain and understand this variance, the concept of BIOAVAILABILITY has been developed.

Question 18

What factors affect bioavailability?

Answer 18

1. the physicochemical characteristics of the drug (ionisation in gut)
2. gastrointestinal pH
3. whether or not the drug is passively or actively transported
4. gastrointestinal motility
5. particle size of the drug
6. physicochemical interaction between drug and gut contents (e.g. chemical interaction between calcium and tetracycline antibiotics)

Question 19

Give some examples of different formulations of aspirin.

Answer 19

aspirin tablets B.P. – ordinary aspirin tablets sold in chemists

soluble aspirin – these are dissolved in water and the solution swallowed

enteric-coated aspirin – these have a sugar and wax coating which remains intact in dilute acid but quickly dissolves in alkali

Question 20

Describe how generics may differ from branded drugs.

Answer 20

Once the patent on a new drug has expired, it is possible for any drug company to manufacture and market the drug. This often means that cheaper examples (GENERIC VERSIONS) of the same drug can be made, in which the formulation is slightly different. However, not all formulations will be equivalent and this can dramatically alter the bioavailability of the drug. Thus, regulatory authorities lay importance on evidence of BIOEQUIVALENCE, that is, evidence that the new ‘generic’ product behaves sufficiently similar to the existing one to be substituted for it without causing clinical problems. This is particularly important when a drug has a narrow (small) THERAPEUTIC INDEX (or THERAPEUTIC WINDOW).

Question 21

What human factors can bioavailability be influenced by?

Answer 21

The drug can be metabolised to inactive products by:

• the microbes within the gut lumen
• enzymes present in the gut wall
• enzymes in the liver

In each of these latter situations, the bioavailability of the drug is altered by what is known a presystemic metabolism or first pass metabolism since the newly absorbed drug does not gain access to the general circulation until it has exited the liver.

Question 22

What is bioequivalence?

Answer 22

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug.

Question 23

What is the therapeutic index?

Answer 23

A quantitative measurement of the relative safety of a drug.

It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.