Pharmacodynamics 2

Question 1

Which of the following initiates the quickest response?
G-protein coupled receptor
Ligand gated ion channel
Intracellular receptor
Tyrosine kinase receptor

Answer 1

Ligand gated ion channel

Question 2

Explain the concepts of drug selectivity and specificity

Answer 2

Many drugs act PREFERENTIALLY on particular receptors or subtypes (selectivity)

No drug is specific i.e. 100% selective for only one receptor subtype.
Specificityof drug action relates to the number of different mechanisms involved.

Assessment of degree of selectivity is important for dosage calculation
e.g. Salbutamol is ~10x more effective in stimulating b2 receptors in airways than b1 receptors in heart

Question 3

Define the term ‘therapeutic index’

Answer 3

The therapeutic index is a comparison of the amount of atherapeuticagent that causes thetherapeutic effect to the amount that causes toxicity

Question 4

Describe the phenomena of desensitization and tolerance

Answer 4

Toleranceis the reduction in response to a drug after repeated administration

Question 5

An antagonist is a drug which _________ the action of an agonist ___________ in the absence of an agonist

Answer 5

inhibits

but has no effect

Question 6

An antagonist is a drug which blocks the response to an agonist. Pure antagonists do not by themselves cause any ‘action’ by binding to the receptor.

What effect does this have on efficacy?

Answer 6

Antagonists have no efficacy.

Question 7

Antagonists can be of two types:

Answer 7

1. receptor antagonists
   a. active site binding (reversible - competitive // irreversible - non-competitive)
   b. allosteric binding ((reversible // irreversible - both non-competitive))
2. nonreceptor antagonists

a. chemical antagonist
(inactivate an agonist before it has the opportunity to act (e.g., by chemical neutralization))

b. physiologic antagonist eg antibodies (physiologic antagonistscause a physiologic effect opposite to that induced by the agonist.)

Question 8

competitive antagonism ________ be overcome by ______________. same maximal response (same Emax) __________ be achieved.

Answer 8

can

by increasing [agonist].

can

Question 9

In the presence of a competitive antagonist - agonist curves features:

Answer 9

Agonist curves have 1. the same form

2. displaced rightwards
3. same maximal response = Emax
4. The linear portion of the curves are parallel

Question 10

Non-competitive //irreversible antagonism ________ be overcome by ______________. Same maximal response (same Emax) __________ be achieved.

Answer 10

cannot

by increasing [agonist]

cannot - even with very high agonist doses

Question 11

In the presence of a irreversible antagonist - agonist curves features:

Answer 11

Agonist curves:

1. do not have the same form
2. Agonist curves have a reduced maximal response (lowered Emax)

Question 12

Examples of Competitive versus irreversible antagonists

Answer 12

competitive:
examples include
bisoprolol at the b1 adrenoceptor

irreversible:
phenoxybenzamine at the a1adrenoceptor.

Question 13

Because no drug is _______ as dose increases the desired response in a patient rises to a maximum beyond which further increases elicit no more benefit but induce unwanted effects (toxic effects)

Answer 13

specific.

you want a SELECTIVE drug so it prevents unwanted side effects

Question 14

Explain difference between graded and quantal dose-response relationships

Answer 14

GRADED
In an individual
Response of a particular system (isolated tissue, animal or patient) measured against agonist concentration

QUANTAL
In a population
Drug (agonist or antagonist) dose required to produce a specified response determined in each member of a population

Percent of a population that responds to a given dose of a drug
(plotted against the drug dose)

Used to determine the effective therapeutic (recommended) dose for a population

Question 15

Therapeutic window (TW) =

Answer 15

= range of doses of a drug that elicits an effective therapeutic response, without unacceptable adverse effects (toxicity)

Question 16

Therapeutic index =

Answer 16

comparison of the amount of atherapeuticagent that causes thetherapeutic effect to the amount that causes toxicity

TI = TD50/ED50

TI =
(dose of drug that causes a toxic response in 50% of the population)
/
(dose of drug that is therapeutically effective in 50% of the population)

Question 17

TI is a measure of a drug’s ________ because _____________

Answer 17

safety

because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Question 18

Drugs with a low therapeutic index (small TW) can be difficult to use unless therapeutic dose monitoring is in operation (e.g. warfarin)

Answer 18

Drugs with a large therapeutic index are generally safe and easy to use (e.g. penicillin)

Question 19

Tolerance is ________

Answer 19

Toleranceis the reduction in response to a drug after repeated administration

Question 20

The two different types of tolerance are:

Answer 20

1. Pharmacokinetic (e.g. altered drug metabolism)
2. Pharmacodynamic:
   a. Receptor internalisation
   b. Receptor down-regulation
   c. Decreased activity of intracellular signalling pathways and ion channels

all of these are tried to be fixed in desensitization.

Question 21

The following are characteristics of drug tolerance:

Answer 21

It is reversible,

the rate depends on the particular drug,
dosage and frequency of use,

differential development occurs for different effects of the same drug.

Question 22

Summary

Answer 22

Antagonists have affinity but NO efficacy

Competitive antagonists:

• Bind reversibly to the receptor
• Antagonism can be overcome by increasing the concentration of the agonist i.e. the same maximal response is achievable
• The agonist dose response curves are shifted to the right in parallel

Irreversible antagonists:

• Bind irreversibly to the receptor
• Antagonism cannot be overcome by increasing the concentration of the agonist i.e. the same maximal response is not achievable

No drug is 100% specific for a particular receptor, so increasing the dose will cause unwanted side effects

The therapeutic index is a measure of a drugs safety; the larger the TI the easier and safer a drug is to use