2. Module 2 # 1 Pharmacodynamics
Kash Desai
HSc A120

3. Drug Receptors and Pharmacodynamics (how drugs work on the body)
The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

4. (how drugs work on the body)2
Pharmacodynamics
(how drugs work on the body)
many drugs inhibit enzymes
Enzymes control a number of metabolic processes
A very common mode of action of many drugs
in the patient (ACE inhibitors)
in microbes (sulfas, penicillins)
in cancer cells (5-FU, 6-MP)
some drugs bind to:
proteins (in patient, or microbes)
the genome (cyclophosphamide)
microtubules (vincristine)

5. Pharmacodynamics 3 most drugs act (bind) on receptors in or on cells
form tight bonds with the ligand
exacting requirements (size, shape, stereospecificity)
can be agonists (salbutamol), or antagonists (propranolol)
receptors have signal transduction methods

6. Drug Receptor
A macromolecular component of a cell with which a drug interacts to produce a response
Usually a protein

7. Types of Protein Receptors
Regulatory – change the activity of cellular enzymes
Enzymes – may be inhibited or activated
Transport – e.g. Na+ /K+ ATP’ase
Structural – these form cell parts

8. dose response curves 5  k 1 [D] + [R] [DR] effect k -1
k1/k-1 = affinity const.
k-1/k1 = dissociation const.(kd)
at equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
the lower the kd the more potent the drug

9. Drug - Receptor Binding
D + R DR Complex
Affinity – measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor
Covalent bonds are stable and essentially irreversible
Electrostatic bonds may be strong or weak, but are usually reversible
Affinity

10. Drug Receptor Interaction
DR Complex
Effect
Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy

11. Drug-receptor interactionk1
Drug + Free Receptor
Drug-receptor Complex D
(100 - DR)
k-1 DR
Where:
D = drug concentration
DR= concentration of drug-receptor complex
100 - DR = free receptor concentration

12. Drug-receptor interaction
At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k-1/k1 = dissociation constant (kd)

13. What can we learn? Ke (k1/k-1) is called the affinity constant
At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k-1/k1 = dissociation constant (kd)
What can we learn?
Ke (k1/k-1) is called the affinity constant
DR is the response; D is concentration of drug
when DR = 50 percent (effect is half maximal), D (or EC50) is equal to kd or the reciprocal of the affinity constant
response is a measure of efficacy
drugs that have parallel dose-response curves often have the same mechanism of action

14. dose response curves-2  6 % occupancy
effect =  [DR] = Emax * [D]/([D]+EC50) 
Concept: spare receptors

15. Arithmetic Dose Scale
Rate of change is rapid at first and becomes progressively smaller as the dose is increased
Eventually, increments in dose produce no further change in effect i.e., maximal effect for that drug is obtained
Difficult to analyze mathematically

16. Log Dose Scale
transforms hyperbolic curve to a sigmoid (almost a straight line)
compresses dose scale
proportionate doses occur at equal intervals
straightens line
easier to analyze mathematically

17. Arithmetic vs log scale of dose

18. Potency Relative position of the dose-effect curve along the dose axis
Has little clinical significance for a given therapeutic effect
A more potent of two drugs is not clinically superior
Low potency is a disadvantage only if the dose is so large that it is awkward to administer

19. Relative Potency Analgesia Dose hydromorphone morphine codeine aspirin

20. Why are there spare receptors?7
Why are there spare receptors?
allow maximal response without total receptor occupancy – increase sensitivity of the system
spare receptors can bind (and internalize) extra ligand preventing an exaggerated response if too much ligand is present
The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC50=kd. Sometimes, full effect is seen at a fractional receptor occupation

21. Agonists and antagonists10
Agonists and antagonists
agonist has affinity plus intrinsic activity
antagonist has affinity but no intrinsic activity
partial agonist has affinity and less intrinsic activity
competitive antagonists can be overcome

22. Agonist Drugs
drugs that interact with and activate receptors; they possess both affinity and efficacy
two types
Full – an agonist with maximal efficacy
Partial – an agonist with less then maximal efficacy

23. Agonist Dose Response Curves
Full agonist
Partial agonist
Response
Dose

24. Antagonist Drug
Antagonists interact with the receptor but do NOT change the receptor
they have affinity but NO efficacy
two types
Competitive
Noncompetitive

25. Competitive Antagonist
competes with agonist for receptor
surmountable with increasing agonist concentration
displaces agonist dose response curve to the right (dextral shift)
reduces the apparent affinity of the agonist i.e., increases 1/Ke

26. Noncompetitive Antagonist
drug binds to receptor and stays bound
irreversible – does not let go of receptor
produces slight dextral shift in the agonist DR curve in the low concentration range
this looks like competitive antagonist
but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect

27. Desensitization 11 agonists tend to desensitize receptors
homologous (decreased receptor number)
heterologous (decreased signal transduction)
antagonists tend to up regulate receptors

28. 8
dose response curves-3 quantal dose response curves (used in populations, response is yes/no)
Therapeutic index =Toxic Dose50/Effective Dose (TD50/ED50)

29. DR Curve: Whole Animal
Graded – response measured on a continuous scale
Quantal – response is an either/or event
relates dose and frequency of response in a population of individuals
often derived from frequency distribution of doses required to produce a specified effect

30. Effectiveness, toxicity, lethality
ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves
TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect
LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects

31. Quantification of drug safety
TD50 or LD50
Therapeutic Index =
ED50

32. Drug A
100
sleep
death
Percent
Responding 50
ED50
LD50
dose

33. Drug B
100
sleep
death
Percent
Responding 50
ED50
LD50
dose

34. The therapeutic index 9 The higher the TI the better the drug.
TI’s vary from: 1.0 (some cancer drugs)
to: >1000 (penicillin)
Drugs acting on the same receptor or enzyme system often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide)

35. Signal transduction 4 enzyme linked ion channel linked
(multiple actions)
ion channel linked
(speedy)
G protein linked
(amplifier)
nuclear (gene) linked
(long lasting)

36. 1. G protein-linked receptors
Structure:
Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices
There’s a G protein attached to the cytoplasmic side of the membrane (functions as a switch).
1. G protein-linked receptors

38. 2. Tyrosine-kinase receptors
Structure:
Receptors exist as individual polypeptides
Each has an extracellular signal-binding site
An intracellular tail with a number of tyrosines and a single å helix spanning the membrane

40. 3. Ion channel receptors Structure:
Protein pores in the plasma membrane

41. Intracellular receptors
Not all signal receptors are located on the plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells.
• The signal molecule must be able to pass through plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).

42. Small, nonprotein, water-soluble molecules or ions
B. Second Messengers
Small, nonprotein, water-soluble molecules or ions
Readily spread throughout the cell by diffusion
Two most widely used second messengers are:
1. Cycle AMP
2. Calcium ions Ca2+

43. 2. Calcium Ions (Ca2+) and Inositol Trisphosphate
Calcium more widely used than cAMP
used in neurotransmitters, growth factors, some hormones
Increases in Ca2+ causes many possible responses:
Muscle cell contraction
Secretion of certain substance
Cell division

44. Two benefits of a signal-transduction pathway 1. Signal amplification
2. Signal specificity
A. Signal amplification
Proteins persist in active form long enough to process numerous molecules of substrate
Each catalytic step activates more products then in the proceeding steps

46. Summary 12 most drugs act through receptors
there are 4 common signal transduction methods
the interaction between drug and receptor can be described mathematically and graphically
agonists have both affinity (kd) and intrinsic activity ()
antagonists have affinity only
antagonists can be competitive (change kd) or
non-competitive (change ) when mixed with agonists
agonists desensitize receptors.
antagonists sensitize receptors.