Theories of drug-receptor interaction

Simple occupancy theory

- Intensity of the response to a drug is directly proportional to the number of receptors occupied
by that drug.
Notes: occupancy of receptor by drug
intensity of response
- Maximal response will occur when all available receptors have been occupied.
- Several limitations:
o Does not account for the potency and maximal efficacy of drugs
o Does not give consider the effect of partial agonists.

Modified occupancy theory

- Recognized the fact that drugs differ in several aspects:

o Ability to bind to the receptor function once binding has taken place (Intrinsic activity)

Affinity

- Strength of attraction b/w drug and its receptor

- The higher the affinity, the greater the strength of attraction
- Reflected in the drugs potency
o Drugs with high affinity are effective in low doses.

Notes: affinity strength of attraction dose

Intrinsic activity

- Ability of a drug to activate a receptor upon binding

- Drugs with high intrinsic activity cause intense receptor activation
- Reflected in drugs maximal efficacy
o Drugs with 1 intrinsic activity have 1 maximal efficacy
Dose-response relationships

- The magnitude of the drug effect depends on the drug conc. at the receptor site
- Types:
o Graded Dose-Response
o Quantal Dose-Response

Graded Dose-receptors

- As the conc. of a drug , its pharmacologic effect also gradually until all the receptors are
occupied (the maximum effect)
- Plotting the magnitude of response against increasing dose of a drug produced a graded dose-
response curve
o Rectangular hyperbola
- Limitations:
o Difficult to construct for a pharmacological response that us quantal (i.e. present/absent
or all-or-none), Example: death, arrhythmia, convulsions
o May not be applicable to other patients
Potency

- Measure of the amount of a drug necessary to produce an effect of a given magnitude

- Determined based on the conc. of drug producing 50% of the maximum effect (EC50)

Efficacy

- Magnitude of response a drug causes when it interacts with a receptor

- Dependent on the no. of drug-receptor complexes formed and the intrinsic activity of the drug
- Maximal efficacy (EMAX)
o Assume that all receptors are occupied by the drug
o No increase in response is observed if a higher conc. of drug is obtained
o Main point of difference b/w a full vs partial agonist
- More clinically useful than drug potency
o Drug with efficacy is more therapeutically beneficial than a drug with potency

Quantal dose-response relationship

- A dose of drug reqd to produce a specified magnitude of effect in a large number of individual
patients is determined first
- The cumulative frequency of distribution of responders is plotted against the logarithm of the
dose
- Plot of dose of the drug and the proportion of a population that responds to it
- Graded response can be transformed to quantal responses by designating a predetermined level
of the graded response as the point at which a response occurs or not.
- Useful for determining doses to which most of the population responds.
- Important in determining the ff:
o Median effective dose (ED50)
o Median toxic dose (TD50)
o Median lethal dose (LD50)
o Therapeutic index
o Therapeutic window

Definition of terms

- Median effective dose (ED50)

o Dose that produces a clinically desired or effective response (ED50) in half the population
- Median toxic dose (TD50)
o Dose required to produce a particular toxic effect in half of the population
- Median lethal dose (LD50)
o If the toxic effect produced above is death

Therapeutic index

- Ration of the dose that produces toxicity in half the population (TD50) to the dose that produces
a clinically desired of effective response (ED50) in the half of the population
- TI = (TD50)/ (ED50)
 - Measure of a drugs safety
o A larger value indicates a wide margin b/w doses that are effective and toxic.

Therapeutic window

- The concentration range range over which drug produce its therapeutic effect.

Drug classification based on intrinsic activity

- Intrinsic activity: ability of drug to activate a receptor binding

- Drug types:
o Agonist
Full/ Strong agonist
Partial/ Weak agonist
Inverse agonist
o Antagonist
Competitive antagonist
Irreversible antagonist
Non-competitive/ Allosteric antagonist
Other types:
Chemical antagonist
Functional antagonist

Full agonist

- Agonist: drug that binds to a receptor and produce a biologic response

- Full agonist
o Drug that binds to a receptor and produces a maximal biologic response (EMax) similar to
the response of the endogenous ligand
o Bind to a receptor, stabilizing it in its active state
o Have an intrinsic activity = 1
o Cause maximal effect despite occupying a small no. of receptors in a cell

Side concept: Spare receptors

- Stephen (1965), while studying the action of acetylcholine, found that full agonists were capable
of eliciting EMax despite occupying a small fraction of receptors, often < 1%
o The largely unoccupied receptors are termed spare receptors or receptor reserves
Common with drugs that elicit smooth muscle contraction

Partial agonist

- Produce lower response at full receptor occupancy than do full agonists

o Even if all the receptors are occupied, partial agonists cannot produce the same EMax as a
full agonist
- Intrinsic activity > 0 but < 1

Inverse agonists

- Have a relative affinity for inactive (R) receptor states and will shift the equilibrium from R* to R
 o Unlike full agonist, stabilize the inactive (R) form and cause R* to convert to R
o Decrease the no. of R* to below that observed in the absence of drug
- Have an intrinsic activity < 0
- Reverse the activity of receptors
- Exert the opposite pharmacological effect of agonists

Antagonist

- Inhibit or block responses cause by agonists

- Bind to a receptor with high affinity but possess zero intrinsic activity
- Types:
Competitive antagonist
Irreversible antagonist
Non-competitive/ Allosteric antagonist
Other types:
Chemical antagonist
Functional antagonist

Competitive antagonist

- Competes with the agonist fir the same binding site a reversible manner
o By binding a receptor, it maintains the receptor in an inactive state and hence prevents
an agonist from binding to the receptor
- The inhibition can be overcome by increasing the concentration of agonist relative to antagonist
o Hence competitive antagonism is surmountable
- Thus, competitive antagonist characteristically shift the agonist dose-response curve to the right
(increased EC50) without affecting EMax

Irreversible antagonist

- Binds covalently to the active site of the receptor, thereby reducing the number of receptors
available to the agonist
- Cause a downward shift of the EMax, with no shift of EC50 values (unless spare receptors are
present)
 - The effect of irreversible antagonists cannot be overcome by adding more agonist
o Hence called Insurmountable
o The rate of antagonist is bound to a receptor, it can no longer be reclaimed by agonist
o According to Lippincott Book: a form of non-competitive antagonist

Allosteric antagonist

- Other books: true non-competitive antagonist

o Binds to a site (allosteric site) other than the agonist-binding site and prevents the
receptor from being activated by the agonist
o Induce a conformational change in the receptor -> agonist no longer recognizes the
agonist-binding domain
- Also cause a downward shift of the EMax, with no shift of EC50 values

Chemical antagonism

- Aka. Neutralization or complexation

o Drugs that binds together when taken at the same time, regarding one or both drugs
inactive
- Example:
o Non-beneficial:
Ca/Mg/Al antacids when taken with tetracycline
o Beneficial:
Chelation therapy (e.g EDTA) during heavy metal poisoning (Pb)
Antidotal therapy of Protamine sulfate (basic) in heparin (acidic) overdose

Functional antagonism

- An antagonist may act at a completely separate receptor, initiating effects that are functionally
opposite those of the agonist
- Example functional antagonism by epinephrine to histamine induced bronchoconstriction:
o Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing
bronchoconstriction.
o Epinephrine agonist at 2-adrenoreceptors on bronchial smooth muscle, causing
bronchodilation
- Aka. Physiological antagonism