Transcript 5th Lecture 1433

PHL 211 Pharmacology
Fifth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
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
(Activated State)
(Resting State)
(Active State)
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
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
(Activated state)
(Resting state)
(Active state)
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
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)
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
Therapeutic Index,
contd.
Why don’t we use a
drug with a T.I. <1?
ED50 > TD50 = Very Bad!
Therapeutic Index (T.I.),
• High therapeutic index
– NSAIDs
• Aspirin
• Tylenol
• Ibuprofen
– Most antibiotics
– Beta-blockers
contd.
• Low therapeutic index
– Lithium
– Neuroleptics
• Phenytoin
• Phenobarbital
– Digoxin
– Immunosuppressives
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
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
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