mechanism of drug action

Question 1

What are the 4 types of drug antagonism?

Answer 1

There are FOUR types of drug antagonism:
•Receptor Blockade
•Physiological Antagonism
•Chemical Antagonism
•Pharmacokinetic Antagonism

Question 2

What is a receptor blockade?

Answer 2

Receptor Blockade

an antagonist binding to a receptor and preventing the binding of an agonist

Question 3

What do receptor blockade depend on?

Answer 3

Use Dependency’
-this refers to ion channel blockers

It means that the more the tissue on which the drug is acting is being
used (the more active they are) the more effective this type of blocker
will be

Question 4

Give an example of how receptor blockade works

Answer 4

Example: normal neurones fire at a relatively low rate so if you put local
anaesthetic on them, there’ll
be relatively low blockage. Nociceptor neurones fire rapidly and because the action potentials are being
generated rapidly so the
ion channels are open more often

Local anaesthetics work by binding to the inside of the ion channels after
they open
-if the channels are opening more often then there is more
chance that they’ll be blocked by LAs

This gives local anaesthetics a selective action on nociceptor neurones - they act on pain conducting fibres more specifically than normal
neurone

Question 5

What is physiological antagonism?

Answer 5

Physiological Antagonism
•Two drugs act at
different receptors
to have opposite effects in the same tissue

Question 6

Give an example of physiological antagonism

Answer 6

•EXAMPLES: NA on the vasculature binds to adrenoreceptors and causes
vasoconstriction. If we coadminister histamine -it acts on different receptors
and causes vasodilation

Question 7

What is chemical antagonism?

Answer 7

Chemical Antagonism

Interaction of drugs in solution

Question 8

Give an example of chemical antagonism

Answer 8

EXAMPLE: Dimercaprol is a chelating agent- it forms heavy metal complexes
which are more rapidly excreted by the kidneys. This is useful for things like
lead poisoning

Question 9

What is pharmacokinetic antagonism?

Answer 9

Pharmacokinetic Antagonism
•When one drug
reduces the concentration
of the other drug at the site of its action
•A drug may reduce the absorption, increase the metabolism or increase the
excretion of another drug
•Must be aware of this so you don’t administer two drugs that interfere with
each other

Question 10

Give an example of pharmacokinetic antagonism

Answer 10

•EXAMPLE: if we repeatedly administer barbiturates we increase the production
of microsomal enzymes so if we administer another drug that is metabolised by
the same enzymes then it is going to be metabolised more quickly and its effect
will be reduced

Question 11

What is drug tolerance?

Answer 11

Gradual decrease in the responsiveness to a drug with repeated administration
e.g. benzodiazepines

Question 12

What are the causes of drug tolerance?

Answer 12

Causes of drug tolerance:
oPharmacokinetic Factors
oLoss of Receptors
oChange in Receptors
oExhaustion of Mediator Stores
oPhysiological Adaptation

Question 13

What do pharmacokinetic factors do?

Answer 13

Pharmacokinetic Factors
•Metabolism of the drug increases when it is given repeatedly over a period of time
•Barbiturates and alcohol are good examples

Question 14

What happens in loss of receptors?

Answer 14

Loss of receptors
•The cell takes receptors off its membrane via
membrane endocytosis
•If the cell is repeatedly stimulated by an agonist, the cell will endocytose some
receptors so there are fewer available on the cell surface
•This is called receptor down regulation
•Beta Adrenoceptors
are susceptible to receptor down-regulation

Question 15

What do change in receptors do?

Answer 15

Change in Receptors
•The number of receptors on the cell surface doesn’t change but the receptors
themselves undergo desensitisation
•Continued stimulation over a long period of time makes the receptors undergo
desensitisation
•This method involves a
conformational change
•So a proportion of the receptors are no longer effective

Question 16

What happens in exhaustion of mediator stores?

-Example

Answer 16

Exhaustion of Mediator Stores
•This is what happens with
amphetamines
•Amphetamine is a central nervous system stimulant- it gets into the blood
steam, crosses the BBB, gets into the brain and it acts on the noradrenergic neurones in the brain
•Amphetamine binds to the uptake 1 protein and gets taken into the central
noradrenaline synthesis system, it replaces the noradrenaline in the vesicles
and you get a big increase in the production of noradrenaline
•If you take a second dose of amphetamine after the first you’ll get a less severe
response because you would
have exhausted the NA stores
-there is no more NA to be released unless it undergoes de novo synthesis

Question 17

What happens in physiological adaptation?

Answer 17

Physiological Adaptation
•This is sort of like a homeostatic response
•The body attempts to maintain a stable internal environment
Tolerance to drugs side effects

Question 18

What are the 4 receptor families?

Answer 18

Type 1 = ion channel-linked receptors
Type 2= G protein couples receptors
Type 3= Kinase-linked type
Type 4= intracellular steroid type receptors

Question 19

What are ion channel-linked receptors?

Answer 19

These are ion channel linked and mediate
VERY VERY FAST
response

Question 20

What are G-protein-coupled receptors?

Answer 20

When you stimulate a type 2 receptor, it has to first link to a G protein
before it can mediate a response
This means that the responses are MUCH SLOWER
oExample: beta-1 adrenoceptors in the heart
Seconds

Question 21

What are type 3 Kinase-linked type receptors?

Answer 21

They result in the phosphorylation of intracellular proteins
oExamples: insulin receptor and growth factor receptors
oMinutes

Question 22

What are type 4 intracellular steroid type receptors?

Answer 22

Activated by steroids and thyroid hormones
Regulates DNA Transcription
The drug has to pass through the cell membrane first and access the nucleus before it can have an effect
oHour

Question 23

Comparing the 4 types of receptors

Answer 23

see table

Question 24

Type 1

• subunits
• defining feature

Answer 24

4 or 5 subunits
Defining feature: transmembrane
sections (alpha helices)
oThere is an external binding
domain that will stimulate and
open the ion channe

Question 25

Type 2

• subunits
• domains

Answer 25

Metabotropic
1 subunit
7 transmembrane domains (7
alpha helices

Question 26

Type 3

-transmembrane domain

Answer 26

Kinase linked
Single protein
1 transmembrane domain
Inside the cell there is an
intracellular domain
When the agonist stimulates the receptor it activates the catalyst inside the cell and stimulates the kinase activity of the receptor leading to
phosphorylation of proteins that leads to a response

Question 27

Type 4

• what type of receptors?
• found where?

Answer 27

Type 4
Steroid receptors
Found in the nucleus
The DNA binding domain is called zinc fingers
When the receptor gets stimulated the zinc fingers get uncovered leading
to DNA binding and an increase in transcription

Question 28

what is first order kinetics?

Answer 28

First Order Kinetics – Most drugs.
§ This describes the rate of elimination of a drug where the amount of a drug decreases at a rate proportional to the concentration of the drug remaining in the body (i.e. slower removal at lower concentrations)

Question 29

what is zero order kinetics?

Answer 29

Zero Order Kinetics e.g. alcohol.
§ This describes a LINEAR rate of elimination of a drug and implies a saturable (enzymatic) metabolic process.
o I.e. The same amount of drug is always removed regardless of the concentration in the volume of distribution.