General Principles of Drug Addiction

Question 1

What is pharmacology?

Answer 1

The study of drugs - what they are, how they work, what they do.
The study of the manner in which the function of living tissues and organs is modified by chemical (including macromolecules - e.g. monoclonal antibodies) substances.

Question 2

Pharmacology comprises of: Pharmacodynamics and Pharmacokinetics, what are these?

Answer 2

Pharmacodynamics is what a drug does to the body (biological effects and mechanisms of action)
Pharmacokinetics is what the body does to a drug (absorption, distribution, metabolism and excretion of drugs and their metabolites).

Question 3

What is the definition of a drug?

Answer 3

Narrowly:
Any single synthetic or natural, substance of known structure used in the treatment, prevention or diagnosis of disease.
More broadly:
Everyday substances (e.g. caffeine, nicotine, ethyl alcohol)
Illicit substances (e.g. cannabis, heroin, cocaine).

Question 4

What is the definition of a medicine?

Answer 4

A chemical preparation containing one, or more drugs used with the intention of causing a therapeutic effect. Medicines usually include agents additional to the active drug.

(A medicine often contains several agents so may consist of several drugs instead of just one.)

Question 5

What must a drug have, to be useful as a therapeutic agent?

Answer 5

For a drug to be useful as a therapeutic agent, it must usually act with a degree of selectivity.

Question 6

What is the definition of selectivity?

Answer 6

Selectivity is the ability of a drug to distinguish between different molecular targets within the body (but this depends upon the dose)

Question 7

Many drugs act by binding to regulatory proteins. What are the main 4 types of regulatory proteins that drugs bind to?

Answer 7

Many drugs act by binding to regulatory proteins, to modify their function, namely:
Enzymes
Carrier molecules (transporters and pumps)
Ion channels
Receptors

Question 8

What are important additional targets of some drugs?

Answer 8

Important additional targets are:

• RNA (Particularly bacterial RNA)
• DNA (mostly older drugs target this)

Question 9

What is very rare for a drug to have?

Answer 9

Vary rarely, a drug has no specific target.

Question 10

Affinity is determined by chemical bonds between a ligand and it’s receptor, what types of bonds are these and what are their strengths in comprasion to each other?

Answer 10

Bonds from strongest to weakest:
Ionic bond
Hydrogenbond
Aromatic (pie-pie)
Van der Waals interaction

Question 11

What is the role of Antagonists?

Answer 11

Bind to receptors (usually reversibly), but do not activate them.
The only step is the affinity or binding step.
It possesses affinity but lacks efficacy and blocks the receptor activation by agonists.
Antagonist lock the effect of receptor activation by agonists.

Question 12

What does selectivity allow drugs to do?

Answer 12

Selectivity allows drugs to interact with select cells and tissues to produce their intended effect by binding to particular molecular targets that they express (and also by binding to different targets within the same cell).

Question 13

There are two cells, Cell type 1 with Target A and cell type 2 with Target B.
How would a drug with total selectivity for target B effect the function of both cells.

Answer 13

A drug with total selectivity for target B would effect the activities of cell type 2 controlled by that target. It would have no effect upon cell type 1.

Question 14

What may be included as targets other than cells and what is an example?

Answer 14

Targets may include those unique to “invaders” such as bacteria, viruses, fungi and parasites.
Penicillin provides an excellent example:
- inhibit an enzyme responsible for cell wall synthesis in bacteria essential to survival.
- Animal eukaryotic cells have neither the enzyme, not a cell wall.

Question 15

What is the definition of a receptor?

Answer 15

Receptors are macromolecules on, or within, cells that mediate the biological actions of hormones, neurotransmitters and other endogenous substances.

Question 16

Drugs acting on receptors are classified as one of two things. What are these?

Answer 16

Agonists and antagonists.

Question 17

What is the definition of an agonist and what is an example of this?

Answer 17

An agonist is a drug that binds reversibly to a receptor to activate them temporarily by inducing a reversible conformation change and 6produce a cellular response.
Adrenaline is a drug (and hormone) that binds to receptors (Beta-adrenoceptors) in the heart to increase cardiac rate and force. It is an agonist.

Question 18

What is the definition of a pharmacological antagonist?

Answer 18

A pharmacological antagonist is a drug that reduces, or blocks, the actions of an agonist by binding to the same receptor..
"Beta-blockers" are a class of drug (synthetic) that binds to Beta-adrenoceptors in the heart to block the binding of adrenaline - they are antagonists and prevent the increase in cardiac rate and force caused by adrenaline.

Question 19

In a reaction where an agonist binds to a receptor what does the reaction posses?

Answer 19

Affinity (K+1 (where the +1 is a subscript)/K-1 (where the -1 is subscript)) and efficacy (Beta/alpha)

Question 20

What is the definition of Efficacy?

Answer 20

It is the ability of an agonist to evoke a cellular response.
If there is a low efficacy the equilibrium is in favour of the reactants and so there will be a small response.
If there is a high efficacy, the equilibrium is in favour of the products and there is a large response.

Question 21

What is another term for the binding step?

Answer 21

Affinity
K+1 (where +1 is subscript) is the rate of agonist binding.
K-1 (where -1 is subscript) is the rate of agonist unbinding.

Question 22

What is another term for the activation step?

Answer 22

Efficacy
Beta = rate of receptor activation
alpha = rate of receptor deactivation

Question 23

What is the result of the reaction if there is a low affinity rate and fast dissociation rate?

Answer 23

The equilibrium is in favour of reactants.

Question 24

If there is medium affinity and a moderate dissociation rate, what is the result of the reaction?

Answer 24

The equilibrium is equal.

Question 25

If the reaction has a high affinity and slow dissociation rate, what is the result of the reaction?

Answer 25

The equilibrium is in favour of the products.

Question 26

Is drug selectivity absolute?

Answer 26

Drug selectivity is rarely absolute (that would be specificity).

Question 27

What affects the ability of a drug to distinguish between different molecular targets?

Answer 27

What is the ability of the drug to distinguish between different molecular targets within the body is critically dependent upon the dose of the drug and frequently the way in which it is administered.

Question 28

How does the example of Salbutamol “Ventolin” explain what affect the ideal dose of a medication have compared to too high a dose?

Answer 28

e.g. salbutamol “Ventolin” an agonist of Beta-adrenoreceptors, given by inhalation I immediate treatment of asthma attack.
The ideal dose acts selectively, “on target”, upon Beta2-adrenoceptors in the airways causing smooth muscle relaxation, the therapeutic intention.
In too high a dose selectivity is lost, now additionally acts “off target” upon Beta1-adrenoceptors in the heart causing unintended increase I cardiac rate, an adverse effect.

Question 29

What is the role of antagonists?

Answer 29

THey bind to receptors (usually reversibly), but do not activate them.
Possess affinity but lack efficacy.
Block receptor activation by agonists.

Question 30

What is the relationship between agonist concentration and receptor occupancy?

Answer 30

As agonist concentration increases the fraction of receptors within a population that are occupied by agonist correspondingly increases.
The relationship between agonist concentration and receptor occupancy is hyperbolic, when plotted on linear coordinates.

Question 31

What is the relationship between concentration (or dose) and effect (or response), which is drawn on a linear plot described as?

Answer 31

Hyperbolic

Question 32

What is EC50 (where 50 is subscript)?

Answer 32

EC50 is the concentration of agonist that elicits a half maximal effect.

Question 33

Something important to note!!

Answer 33

Note the indentity to Michaelis-Menten enzyme kinetics previously taught where the relationship between substrate concentration (S) and reaction velocity(V) is also hyperbolic. Here, agonist concentration (A) and effect (E) replace (S) and (V), respectively. EC50 is similar to Km, the Michaelis constant, which is he concentration of substrate at which the velocity of the reaction is half maximal.

Question 34

What is the relationship between concentration (or Dose) and Effect (or response) on a semi-logarithmic plot described as?

Answer 34

Sigmoidal

Question 35

What is the definition of potent?

Answer 35

To have a great, power, influence or effect.

Question 36

How can you tell whether an agonist has a high or low potency?

Answer 36

The higher the potency of an agonist, the lower the agonist concentration needed to reach the maximum effect. The opposite it the case if an agonist has a low potency.

Question 37

How can you tell whether an agonist has a low or high efficacy?

Answer 37

The higher an agonist’s efficacy, the higher the maximum effect.

Question 38

What is the process of reversible competitive antagonism?

Answer 38

Thebinding of an agonist and antagonist, both of which are reversible, occur at the same (orthosteric) site and is thus competitive and mutually exclusive.
Reversible competitive antagonism can be overcome by increasing the concentration of agonist.

Question 39

What is the process of non-competitive antagonism?

Answer 39

An agonist binds to the orthosteric site and antagonist binds to a separate allosteric site and thus is not competitive. Both may occupy the receptor reversibly and simultaneously, but activation cannot occur when antagonist is bound.

Question 40

What effect do antagonists have of an agonist concentration response curve?

Answer 40

Competitive antagonists cause a parallel rightward shift of the agonist concentration response curve but maximum response is unchanged.

Question 41

What effect do non-competitive antagonists have on the concentration response curve.

Answer 41

Non-competitive antagonists depress the slope and maximum of the concentration response curve, but do not cause a rightward shift.

Question 42

What effect does increasing the concentration of a competitive antagonist have on an agonist concentration response curve?

Answer 42

Progressive rightward shift of agonist concentration response curve on concentration axis, but not depression of slope, or maximum response.

Question 43

What is the effect of increasing the concentration of a non-competitive antagonist on an agonist concentration response curve?

Answer 43

Progressive depression of maximum response and slope, but no shift of agonist concentration response curve on the concentration axis.

Question 44

What do receptors mostly consist of?

Answer 44

Protein macromolecules.

Question 45

How do agonists work and what do they posses?

Answer 45

Agonists activate receptors to initiate cellular responses. They possess affinity and efficacy.

Question 46

Do partial agonists have the same efficacy and potency as full agonists?

Answer 46

They may have the same potency but will have a lower efficacy than full agonists.

Question 47

How do antagonists work and what do they posses?

Answer 47

Antagonists bind to receptors and block the effect of antagonists. They possess affinity, but not efficacy.

Question 48

Do Antagonists act competitively or non-competitively?

Answer 48

Antagonists may act either competitively, or non-competitively.