1. Brief Review of Dr. Swanson’s and Dr. Prakriya’s material
Selected Important Points

2. Competitive antagonists and D-R curves
bind reversibly to the same site as agonists
increasing concentration of agonist overcomes effect of the antagonist
parallel shift to the right
of DR curve
potency (EC50)
efficacy unchanged
SURMOUNTABLE by
increasing
the agonist concentration

3. Noncompetitive antagonists and D-R curves
bind irreversibly to the same site as agonists OR to a distinct (allosteric) site on the receptor to reduce function
increasing concentration of agonist does not overcome effect of the antagonist- not SURMOUNTABLE
depression of Effectmax
in DR curve
 efficacy
potency unchanged
This is the
idealized situation
e.g., if ion channel
currents are being studied

4. What happens for FULL AGONISTS when an intricate signal transduction pathway intervenes?
SPARE RECEPTORS

5. Spare receptors
In some systems, a maximum response can be achieved with less than 100% receptor occupancy because “spare” receptors exist
for full agonists because of amplification via signal transduction cascades.
EXAMPLE OF SPARE RECEPTORS:
●Histamine causing
smooth muscle contraction
via the phospholipase C pathway
●ACh causing skeletal muscle
contraction (spare receptors
for contraction and even action potentials)

6. Spare receptors and D-R curves
In the presence of spare receptors, low concentrations of noncompetitive antagonists can produce dose-response curves similar to those of competitive antagonists
So how do we distinguish a true competitive antagonist from any other type of antagonist (e.g. irreversible or non-competitive)? Answer: We continue to take up the concentration of antagonist. A true competitive antagonist will continue to produce a parallel shift to the right of the log dose-response curve WITHOUT A CHANGE IN MAXIMUM regardless of how high its concentration is raised. The other types of antagonists will not (see slide #8).

7. ANSWER: TAKE UP THE DOSE OF ANTAGONIST-see the next slide
So how does one distinguish a true competitive inhibitor from an irreversible antagonist (as both types of agents produce a parallel shift to the right in the agonist log dose response curve?
ANSWER: TAKE UP THE DOSE OF ANTAGONIST-see the next slide

8. Spare receptors and D-R curves
In the presence of spare receptors, low concentrations of noncompetitive antagonists can produce dose-response curves similar to those of competitive antagonists
Now at the higher concentration of antagonist non-competitive and irreversible inhibitors reduce the maximum response of the full agonist but true competitive inhibitors do not change the maximum.

9. Quantal dose response curves: more relevant clinically
Quantal D-R curves
all-or none responses such as death, pregnancy, convulsions, etc.
The raw data (which will then be summed progressively)

10. Quantal dose response curves: more relevant clinically
Quantal D-R curves
all-or none responses such as death, pregnancy, convulsions, etc.
expressed as cumulative percent
ED50 is the mean effective dose at which 50% of individuals exhibit the specified effect.

11. You want drugs with a big T.I.
The therapeutic index and drug side-effects
The Therapeutic Index is a measure of drug safety.
If death is the measure, the Toxic ED50 is also known as the Median Lethal Dose (LD50).
Therapeutic index=
Toxic ED50/ Beneficial ED50
You want drugs with a big T.I.
=LOW ED50 for Beneficial Effect-small number in denominator=big TI

12. Some electrophysiological principles-changes in membrane potential and excitation.
1) A CONDUCTANCE INCREASE (the naturally occurring phenomenon).
2) WHEN THE EXPERIMENTALIST CHANGES ION CONCENTRATIONS.
One aspect of the Pharmacology part of Foundations 2 that I would like to review relates to difference between changes in membrane potential due to: 1) A CONDUCTANCE INCREASE (the naturally occurring phenomenon) vs 2) WHEN THE EXPERIMENTALIST CHANGES ION CONCENTRATIONS. I brought a different channel model to the lecture (one of a voltage-gated sodium channel) to illustrate 1 (see next slide)

13. Some electrophysiological principles-changes in membrane potential and excitation.
1) A CONDUCTANCE INCREASE (the naturally occurring phenomenon).
One aspect of the Pharmacology part of Foundations 2 that I would like to review relates to difference between changes in membrane potential due to: 1) A CONDUCTANCE INCREASE (the naturally occurring phenomenon) vs 2) WHEN THE EXPERIMENTALIST CHANGES ION CONCENTRATIONS. I brought a different channel model to the Plenary (one of a voltage-gated sodium channel) to illustrate 1 (see next slide)

14. The message is that, by Ohm’s Law, in order to get an ionic current, I (movement of charged yellow balls/unit time in the model) we need both a conductance increase, g (Na channels must be opened by the appropriate stimulus-in this case depolarization), and a driving force, delta V (namely a difference between where the membrane is sitting at rest (Vm=-70 mV) and the equilibrium potential or Nernst potential for sodium (ENa=+67 mV =the floor of the classroom in my model). There is no current if there is no driving force (no delta V) or if the channel is closed (g=0)-i.e. both a driving force and open channels are required. So the best way to change membrane potential is to open channels (increase g) for an ion that is far away from equilibrium at rest (Na, i.e. an ion that has a large difference between where it is and where it wants to be). This channel opening then lets Na into the cell down its electrochemical gradient and by adding + charge added to the internal face of the membrane capacitance, depolarizes the cell as its drives the membrane potential towards the equilibrium potential (Nernst potential) for sodium ions (things in nature try to reach an equilibrium). This is how action potentials are generated.

15. Does an action potential change Na+ concentrations?
IT DOESN’T!!!!!
The Nernst potential does not change.
It takes picomoles (10-12 moles) of Na to produce and action potential and there is 145 mM Na out and 10 mM Na in. Hence we generally do not consider changes in ion concentrations when we talk about ion channels opening and the resulting ion movements changing membrane potentials. The exception is when the nerve fiber is very small and huge numbers of action potentials are fired, (whereby ion concentrations may change and ion pumps may come into play to restore ionic gradients). More specific details follow.
You heard from Dr. Prakriya about the need for positive and negative charges being equal, i.e. electroneutrality. This is indeed the case for the bulk solution where large concentrations of ions are present-this is termed macroscopic electroneutrality and is certainly true.  At the membrane, the charge separation appears to violate this principle of electroneutrality and indeed it does. The reason this can happen is that the concentration changes produced by the charge separation at the membrane cannot possibly be measured as it is in essence negligible. If we say the cell has a resting Vm of -85 mV, a radius of 25 um, then there is actually an excess of ~7 X moles of excess negative charge on the internal face of the membrane. If one distributed negative charge excess in the bulk solution, they would be at a 10-9 M concentration or one part in 10^ 8 of the total concentration of anions-thus negligible. Hence a small amount of ion movement across membranes can create considerable potential changes without changes in the bulk concentration of ions. Dr Prakriya has a slide of a similar sort calculation for sodium movement during and action potential, again the change in concentration is negligible.

16. Some electrophysiological principles-changes in membrane potential and excitation.
1) A CONDUCTANCE INCREASE (the naturally occurring phenomenon).
2) WHEN THE EXPERIMENTALIST CHANGES ION CONCENTRATIONS.

17. 2) WHEN THE EXPERIMENTALIST CHANGES ION CONCENTRATIONS.
Now the Nernst potential change drives membrane potential changes if a channel is available for a particular ion.
Hence a decrease in extracellular sodium by the experimentalist from 145 mM to a lower value will make the action potential smaller.

18. What does an decrease in the concentration of extracellular sodium ions do to the size of the action potential?
Think about it. Answer in class.
Please see previous slide notes.

19. What does an increase in extracellular potassium ion concentration do to the membrane potential? Think about it. Answer in class.
Answer in class.

20. Good luck on the FND2 module exam☻