pharmacology 2

Question 1

How are drug effects quantified? And how is this relationship described?

Answer 1

By studying the relationship between drug concentration (or dose) and the response produced by the drug.

This relationship is described by concentration-response curves.

Question 2

What are the three main types of pharmacological experiments?

Answer 2

In vitro

In vivo

Ex vivo

Question 3

Experiments in vitro - how are the drug effects studied?

Answer 3

On a piece of tissue dissected from an animal (or human) and kept alive outside the body

This is by far the most common type of experiment

Includes experiments on cells grown in tissue culture.

Question 4

Experiments in vitro - what are the responses that might be measured?

Answer 4

Changes in tension of a muscle

Changes in the activity of an enzyme

Changes in the secretion of a hormone or neurotransmitter

Question 5

In vivo experiments- how are the drug effects studied?

Answer 5

In the living animal (or human)

Include clinical trials

Tightly regulated by the Home office in the UK

Question 6

In vivo experiements - what are the responses that might be measured?

Answer 6

Increase in blood pressure

Reduction in pain threshold

Reduction in allergen-induced bronchoconstriction

Question 7

Ex vivo experiments- how are the drug effects studied?

Answer 7

A tissue or organ is removed from an animal that has been treated with a drug

The effects the drug has had on organ function are tested in vitro

This is also very tightly regulated by the Home Office

Question 8

Examples of ex vivo experiments

Answer 8

Examples might include experiments to see whether longterm treatment with a drug induces liver damage or alters some aspect of brain biochemistry

Question 9

(log) concentration- response curve- the concentration axis

Answer 9

Invitro= concentrations are expressed in Moles per litre I.e Molar (M)

1 mole of a drug contains 6.02 x 10^23 drug molecules and weighs the molecular mass, in grams

A 1 Molar solution contains 1 Mole of a drug dissolved in 1 litre of solvent

Most importantly, a 1 Molar solution of a drug “X” will contain the same number of drug molecules as a 1 Molar solution of drug “Y”

Question 10

What suggests a drug is clinically useful?

Answer 10

It acts at a very low concentrations.

Question 11

At what concentration range do most drugs act at?

Answer 11

Most drugs act at concentrations in the range 1 x 10-6M to 1 x 10-12M i.e. they are very potent (see later)

Question 12

How many drug molecules per litre does a 10-9 M solution of drug contain?

Answer 12

Bear in mind however that a 10-9 M solution of drug still contains 6.02 x 1014 or 602000000000000 drug molecules per litre!

Question 13

Often pharmacologists will use the prefixes milli (m)- micro () - and nano (n)- for 10-3 ,10-6 , and 10-9 respectively. How to convert between them?

Answer 13

……

thus 1 micromolar (M) solution is the same as a 1 x 10-6 M solution

Question 14

Constructing a concentration-response curve

Answer 14

Question 15

Constructing a concentration- response curve

Answer 15

Question 16

Constructing a cumulative concentration-response curve

Answer 16

Question 17

Doses in vivo - why is it not possible to use molar concentrations? How are drug doses expressed?

Answer 17

Because the volume of the solvent (e.g blood) is not known

As weight of drug per weight of animal e.g 1mg per kg (1mgkg-1)

This allows an approximate extrapolation of the dose from, for example, a 20-gram mouse to a 70 kg human.

Question 18

(log) concentration-response curve- what is the maximum effect (Emax)?

Answer 18

Indicates the maximum response (effect) the drug can produce

It is the top of the curve, where increasing the concentration of the drug produces no greater effect.

Question 19

(log) concentration- response curve- What is the EC50?

Answer 19

Tells us the position of the curve on the concentration axis.

Defined as “the Molar concentration of a drug that produces 50% of the maximum response for that drug”

Sometimes use other percentage values such as EC90 or EC20

Question 20

What is potency?

Question 21

What is a potent drug?

Answer 21

A drug that is effective in very small amounts

Question 22

What does a lower EC50 mean for the potency of a drug?

Answer 22

Lower EC50 value means the drug is more potent.

Question 23

How to calculate the relative potencies of two drugs with the same action ?

Answer 23

• Compare their EC50 values described by the potency ratio (M)
• Often we will be comparing a new drug (the test drug) with a drug that is already available (the standard drug)

Question 24

M and log M equations

Answer 24

M = EC50(test)/EC50(standard)

log M = logEC50(test) – logEC50(standard)

Question 25

What does a value of M less than 1.0 mean?

Answer 25

Means that the test drug is more potent than the standard

Question 26

What is bioassay?

Answer 26

* A “bioassay” is any technique where the ***potency*** of a drug is determined by ***measuring*** the biological ***response*** it produces * Pharmacologists have developed hundreds of different bioassays, ranging from cells growing in tissue culture to clinical trials in humans to look at different aspects of drug responses * Bioassays underpin the development of new drugs in the pharmaceutical industry

Question 27

What is the "2+2" bioassay?

Answer 27

* The simplest bioassay for determining the relative potency of two drugs * Makes use of the fact that the middle portion of the log concentration-response curves are almost linear, and if the two drugs are acting by the same mechanism, then the lines should be parallel.

Question 28

How can M be obtained in "2+2" bioassay?

Answer 28

By comparing two doses of standard (S1, S2) with two doses of unknown (U1,U2)

Question 29

A clinical example - morphine vs codeine

Answer 29

Question 30

What is the therapeutic index?

Answer 30

The ratio between the toxic dose of a drug and the dose producing the desired therapeutic effect

Question 31

What does a higher therapeutic index mean for side effects?

Answer 31

The higher the therapeutic index, the less chance of the drug producing toxic side-effects in therapeutic use.

Question 32

How is the therapeutic index defined?

Answer 32

therapeutic index = LD50/ED50 LD50= Lethal dose in 50% of population ED50 = Effective dose in 50% of the population

Question 33

Why is the therapeutic index no longer used?

Answer 33

It is a meaningless definition from a clinical perspective. Death is a rather extreme side effect. Ethically it is no longer defensible to obtain LD50 values in animals

Question 34

How can the therapeutic index be calculated in humans?

Answer 34

TD50/ED50

Question 35

What is TD50?

Answer 35

The"toxic" dose in 50% of the population, where we look for the dose that produces some sign of toxicity e.g. causes nausea.

Question 38

Therapeutic index - Why do we still have to treat it with caution?

Answer 38

* There is a wide person to person variation in the both toxic and beneficial effects of drugs * A drug can have different ED50 values depending on the condition being treated e.g. the effective dose of ibuprofen for treating headache is lower than that for treating arthritis