1. PHL 211 Pharmacology
Fifth Lecture By Abdelkader Ashour, Ph.D. Phone:

2. Drug Receptor Interactions, The two-state model of receptor activation
The receptor is in two conformational states, ‘resting’ (R) and ‘active’ (R*), which exist in equilibrium
Normally, when no ligand is present, the equilibrium lies far to the left, and a few receptors are found in the R* state
For constitutively active receptors, an appreciable proportion of receptors adopt the R* conformation in the absence of any ligand
Agonists have higher affinity for R* than for R and thus shift the equilibrium from the resting state (R) to the active (R*) state and hence, produce a response
(Resting State)
(Active State)
(Activated State)
Agonist

3. Drug Receptor Interactions, Inverse agonist
Inverse agonist “An agent which binds to the same receptor binding-site as an agonist for that receptor but exerts the opposite pharmacological effect”
Difference from Antagonist: Antagonist binds to the receptor, but does not reduce basal activity
Agonist  positive efficacy
Antagonist  zero efficacy
Inverse agonist  negative efficacy
Inverse agonists are effective against certain types of receptors (e.g. certain histamine receptors and GABA receptors) which have constitutive activity
Example 1: the agonist action of benzodiazepines on the benzodiazepine receptor in the CNS produces sedation, muscle relaxation, and controls convulsions. b-carbolines (inverse agonist) which also bind to the same receptor cause stimulation, anxiety, increased muscle tone and convulsions
Example 2: the histamine H2 receptor has constitutive activity, which can be inhibited by the inverse agonist cimetidine. On the other hand, burimamide acts as a neutral antagonist

4. Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist
An inverse agonist has higher affinity for R than for R* and thus will shift the equilibrium from the active (R*) to resting state (R) state
A neutral antagonist has equal affinity for R and R* so does not by itself affect the conformational equilibrium but reduces by competition the binding of other ligands
In the presence of an agonist, partial agonist or inverse agonist, the antagonist restores the system towards the constitutive level of activity
Inverse Agonist Antagonist
(Resting state)
(Active state)
(Activated state)
Agonist

5. Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist, contd.
An inverse agonist has higher affinity for R than for R* and thus will shift the equilibrium from the active (R*) to resting state (R) state
A neutral antagonist has equal affinity for R and R* so does not by itself affect the conformational equilibrium but reduces by competition the binding of other ligands
In the presence of an agonist, partial agonist or inverse agonist, the antagonist restores the system towards the constitutive level of activity

6. Drug-Receptor Bonds and Selectivity
Drugs which bind through weak bonds to their receptors are generally more selective than drugs which bind through very strong bonds
This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur
Only a few receptor types are likely to provide such a precise fit for a particular drug structure
To design a highly selective short acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds
Selectivity:
Preferential binding to a certain receptor subtype leads to a greater effect at that subtype than others
-e.g. salbutamol binds at β2 receptors (lungs) rather than at β1 receptors (heart)
Lack of selectivity can lead to unwanted drug effects.
-e.g. salbutamol (b2-selective agonist ) vs isoprenaline (non-specific b-agonist) for patients with asthma. Isoprenaline  more cardiac side effects (e.g., tachycardia)

7. Therapeutic Index (T.I.)
A measure of drug safety
The ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals
Therapeutic Index = TD50/ED50 or LD50/ED50
where TD50is the dose that produces a toxic effect in 50% of the population, LD50 is the dose that is lethal in 50% of the population and ED50 is the dose that produces therapeutic response in 50% of the population
In general, a larger T.I. indicates a clinically safer drug
TD50

8. Therapeutic Index, contd.
Why don’t we use a
drug with a T.I. <1?
ED50 > TD50 = Very Bad!

9. Therapeutic Index (T.I.), contd.
High therapeutic index
NSAIDs
Aspirin
Tylenol
Ibuprofen
Most antibiotics
Beta-blockers
Low therapeutic index
Lithium
Neuroleptics
Phenytoin
Phenobarbital
Digoxin
Immunosuppressives

10. Spare Receptors
Pool of available receptors that exceeds the number required for a full response
In some systems, full agonists are capable of eliciting 50% response with less than 50% of the receptors bound (receptor occupancy)
Maximal effect does not require occupation of all receptors by agonist.
In these systems, low concentrations of competitive irreversible antagonists may bind to receptors and a maximal response can still be achieved
Common for receptors that bind hormones and neurotransmitters
If [R] is increased, the same [DR] can be achieved with a smaller [D]
A similar physiological response is achieved with a smaller [D]
Economy of hormone or neurotransmitter secretion is achieved at the expense of providing more receptors

11. Desensitization (Tachyphylaxis) and Tolerance
The loss of a drug’s effect, when it is given continuously or repeatedly
On a short time-scale, such as a few minutes, this situation is called desensitization or tachyphylaxis and on a longer time-scale, such as days or weeks, the term tolerance is preferred
Receptor-mediated responses to drugs and hormonal agonists often desensitize with time, when they are given continuously or repeatedly
After reaching an initial high level, the response (e.g., cellular cAMP accumulation, Na+ influx, contractility, etc) gradually diminishes over seconds or minutes, even in the continued presence of the agonist
This is usually reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response
Example: chronic salbutamol (b2 agonist) can cause internalisation of receptors → less receptors available for stimulation (down-regulation) → decreased bronchodilation
Why desensitization?
Many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods

12. Idiosyncrasy
A structural or behavioral characteristic peculiar to an individual or group
Idiosyncratic drug reaction is a qualitatively abnormal, and usually harmful, drug effect that occurs in a small proportion of individuals
In many cases, genetic materials are responsible
Example:
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that maintains the content of reduced glutathione (GSH) in red blood cells, and thus prevent hemolysis
Individuals with G6PD deficiency cannot tolerate oxidant drugs e.g., primaquine, some sulfonamide drugs, .. (well tolerated in most individuals)
Those individuals will suffer from hemolysis leading to severe anemia
Primaquine and related substances reduce red cell GSH harmlessly in normal cells, but enough to cause hemolysis in G6PD-deficient cells
GSH
GSSG