1. Bruce Wainman, PhD

2. Drugs and Marketing Drugs are often marketed as the most potent, the most efficacious, the most effective and the best tolerated The words efficacy and potency have real pharmacological definitions which we will talk about today The effectiveness of drugs in a populations is evaluated in a number of different ways and you can always bet that the drug when it is marketed will be shown in the best possible light

3. Drugs normally have to bind receptors before they have an effect. This drug would have its effect through a second messenger system but only after it bound to its receptor Drug or natural ligand Receptor Drug-receptor complex Drugs and Receptors

4. Kinetics… DrugReceptors Drug binds to receptor, the rate of this occurrence is k 1 Drug dissociates from receptor, the rate of this occurrence is k -1. The drug rapidly binds to the receptor and slowly dissociates thus it has high affinity for the receptor. Drug quickly dissociates from receptor and never really binds very well which is to say that k 1 is slow and k -1 is fast. The drug has a low affinity for this receptor.

5. Drug Receptor Complex- The Rate of Formation R = receptor, X = drug and RX = drug receptor complex R + X RX Rate of the formation of RX is called k 1

6. Drug Receptor Complex- The Rate of Breakdown The drug-receptor reaction is reversible so: RX k -1 R + X will also occur The ratio of the rate of breakdown to the rate of formation is called the K d –i.e., k -1 /k 1 = K d –K d is also called the dissociation constant –The reciprocal of K d (i.e., (k 1 /k -1 ) is called affinity –Drugs with low K d have high affinity In the end we set up a nice old fashioned equilibrium governed by the rate of breakdown and the rate of construction of drug-receptor complex. [R] + [X] [RX] k1k1 k -1

7. [R][X][RX]k1k1 k -1... = [R] + [X] [RX] k1k1 k -1 Sooooo, if we have an equilibrium like this: Then it must mean that rate of formation of the drug receptor complex and the breakdown of the drug receptor complex are equal. The way we write this arithmetically is to multiply the available drug and receptor times the forward rate constant and make it equal to the rate of the breakdown of the drug receptor complex so it looks like this:

8. The neat thing about this is that if you take this formula …. [R][X][RX]k1k1 k -1... = [R][X][RX]k1k1 k -1... = k1k1 k1k1 [R][X]. = [RX]k -1. k1k1 Divide by k 1

9. Almost there…. [R][X]. = [RX]k -1. k1k1 [R][X]. = [RX] KdKd Substitute Kd for k-1/k1. Divide both sides by [RX] [RX][RX] KdKd [R][X]. = [RX] Ta dah! The dissociation rate constant is equal to the amount unoccupied receptors and unbound drug divided by the concentration of drug-receptor complex. The significance is that drugs that bind well have lots of RX and lots of affinity. = [RX] KdKd.

10. Affinity Affinity (how well the drug sits in the receptor) does not tell you anything about the action of the drug. Really Really, really Nothing…. Agonism is the the thing

11. Agonism Agonists –Bind the same site as the endogenous ligand and produces the same signal as the endogenous ligand* e.g., dexamethasone (a long acting glucorcorticoid) can give the same response as cortisol –If the full effect can be elicited the drug is said to be a full agonist or that it has high efficacy –If only part of the effect is elicited then it is said to be a partial agonist e.g., methadone only gives part of the effect heroin * a ligand is simply something that binds the receptor

12. Log of Drug Concentration Percent of Maximum Biological Effect 100 0 50 The Dose Response Curve EC 50

13. Log of Drug Concentration Percent of MaximumBiological Effect 100 0 Equal in Efficacy and Full Agonists Partial Agonist 50 EC 50 ?EC 50 EC 50

14. Affinity If the three drugs on the previous page differ in EC 50 * and act at the same receptors then it is likely that they differ in affinity for the receptor. * The EC 50 is the concentration required to give half the maximal effect for that drug

15. Agonists- the Sequel Antagonists: –Bind the same site as the endogenous ligand and do not produces the same signal as the endogenous ligand e.g., propranolol blocks the ß-adrenoceptor so that epinephrine and norepinephrine cannot bind Antihistamines block the histamine receptor. –An antagonist that has no efficacy is an antagonist (you don’t have to say “complete antagonist” that is redundant)

16. Antagonism There are two types of antagonism, one type is reversible and the other is irreversible. Reversible Antagonism comes in a number of forms. –Competitive antagonism occurs when the antagonist competes for the same receptors as the agonist but the antagonist will dissociate from the receptor If you are keeping track, that means that k -1 > 0 –Since it is a competition the antagonist can always “lose” if there is enough of the agonist You can imagine the antagonist being diluted out by enough agonist.

17. 100 Log of Drug Concentration 0 Percent of Maximum Biological Effect 50 Agonist alone Agonist plus competitive antagonist Agonist plus more competitive antagonist 0

18. Noncompetitive Antagonism If the antagonist binds to a site other than the receptor and keeps the agonist from having an effect at the receptor it is called a noncompetitive antagonist PCP (phenylcyclidine, “angel dust” or “hog”) and ketamine (KETALAR or “Special K)” are noncompetitive antagonist of the NMDA receptor and hallucinogens. O/D on PCP is untreatable and often results in permanent brain damage Ketamine is somewhat less toxic and still used as a pre- anaesthetic Noncompetitive antagonists are very useful experimentally but almost useless clinically, why?

19. Irreversible Antagonism If the antagonist binds to the receptor or near the receptor and does not let go then it is called irreversible antagonism Irreversible cholinesterase inhibitors (“nerve gases”) work this way Acetylcholine ACh-ase acetate + choline If there is no cholinesterase then acetylcholine builds up in nicotinic and muscarinic cholinergic synpases. The nicotinic effects include muscle fasiculations and fatigue. The muscarinic effects look like overstimulation of the parasympathetic nervous system and include salivation, cardiovascular depression etc. ASA is very nearly a irreversible (some call it pseudo-irreversible) The enzyme cyclo-oxygenase (COX) is acetylated by aspirin and will not work to make prostaglandins for and irreversible antagonist the rate of breakdown of the drug-receptor complex is zero, i.e., k -1 = 0 if this is the case then K D = if very low… thus affinity is very high (perhaps infinite if the drug never lets go of the binding site) Irreversible antagonists are very useful experimentally but almost useless clinically, why?

20. Log of Drug Concentration 100% 0% Agonist with increasing doses of antagonist Percent of Maximum Biological Effect

21. Log of Drug Concentration 100% 0% Agonist with increasing doses of antagonist Percent of Maximum Biological Effect Agonist with a large dose of irreversible antagonist or a noncompetitive antagonist

22. Potency Potency ompares the effective concentration of a drug in producing a therapeutic effect with drugs acting in a similar fashion –Usually drugs are compared on the basis of their EC 50s Potency is particularly important when speaking about the whole organism If a drug is highly potent it has "good bang for the buck," i.e., it does not take much drug to get a full effect Normally potent drugs have really high affinity for the receptor –Because potent drugs have high affinity it doesn’t take many molecules to find and bind their receptors

23. Log of Drug Concentration Percent of Maximum Biological Effect 100% 0% 50% Most potent Much Less potent Less potent EC 50

24. Log of Drug Concentration Percent of Maximum Biological Effect 100% 0% 50% Much Less potent and lower efficacy Less potent but high efficacy Most potent but lower efficacy

25. Physiological Antagonism This occurs when you take a drug to counteract the effects of another drug A good example of this is when you consume caffeine to lessen the effects ethanol intoxication –Essentially you end up being a wide awake drunk. This type of antagonism has nothing to do with competition for receptors sites or even binding to sites away from the receptor as in noncompetitive antagonism, it is strictly about counteracting the effects of one drug with another working by a separate physiological mechanism.

26. Activity of Acyclovir(ZOVIRAX) Against Viral Growth HSV 1 = herpes simplex virus Type 1, HCMV = human cytomegalovirus

27. The Dose Response Curve- Quantal Effects Many responses to drugs, especially in intact organisms are quantal, i.e., the response is either there or not –When you feel unwell the utility of the drug is measured as whether it works or it does not. –The answer to the following questions are all yes or no. Does this drug provide adequate pain relief? Does this drug remove your headache? Do you still feel depressed after taking this drug? –The responses to the questions are all quantal The dose response curve is the the sum of those responding to treatment at increasing does The measurement of potency in this case is the effective dose to treat 50% or the ED 50

28. Ninety people suffering from a headache were given a dose of headache medication and asked the question, is your headache gone? The x-axis is the number of positive responses to the question at a particular dose. The medication was given at 1mg increments and the question was asked again until the 20 mg dose was attained. If a positive response was achieved the person was finished participating in the experiment. In this example you will notice that 1/ there is a normal distribution of responses and 2/ that by the time we get to 20 mg almost everyone has responded to a lesser dose of medication.

29. S u m of R e s p o n s e s Dose (mg) This is the same data as the last graph. The difference here is that I have summed all the people who have responded on the y-axis. For example, at an 11 mg dose of drug a total of 40 people have lost their headaches. Notice that less than the whole study population has responded to the drug.

30. Cummulative Biological Response 100 The Dose Response Curve- Quantal Effects Log of Drug Dose 0 50 ED 50 This is the same data as the last two graphs. The difference here is that I have expressed the response data as a percentage of the population participating. I have converted the dose data to a log of the dose. With this sort of curve we can easily calculate the ED 50

31. Activity of Vincristine (ONCOVIN) Against Tumour Cell Lines Cell Mortality (%) What sort of dose/response curve is this? Catharanthus roseus (Madagascar Periwinkle)

32. Dose (mg) Activity of Morphine, Ibuprofen (ADVIL) and ASA (ASPIRIN) for Pain Control What sort of dose-response curves are these?

33. Fluoxetine = PROZAC Amitriptyline = ELAVIL

35. Therapeutic Index and Therapeutic Window Between a rock and a hard place….

36. Log of Drug Dose Percent Experiencing the Biological Effect 100% 0% 50% Dose- response curve for therapeutic effect Dose- response curve for toxicity ED 50 LD 50 The Therapeutic Window

37. Log of Drug Dose Percent Experiencing the Biological Effect 100% 0% 50% ED 50 LD 50 Dose- response curve for therapeutic effect Dose- response curve for toxicity The Therapeutic Window

38. Therapeutic Index The therapeutic index of a medication is a quantitative measure that compares the amount of drug that causes the therapeutic effect to the amount that causes the toxic effects. One measure of therapeutic index is to use lethal dose for 50% of the population (LD50) and divide this by effective dose of a drug for 50% of the population (ED50). The use of the LD50/ED50 ratio is not really that useful since we are often more interested on the onset of side effects or toxicity not just lethality. Therapeutic indices using the onset of toxic effects compared to the ED50 may also be used. In the USA they refer to drugs with narrow therapeutic windows as having a narrow therapeutic index (i.e., “an NTI”) but what they mean is a low therapeutic index.

39. Therapeutic Index Examples The drug digoxin (a chemical called a glycoside which comes from the plant Digitalis purpurea) has a therapeutic index of between 2 and 10 There are a relatively small number of these drugs which you may see in midwifery and obstetrics but they include: Warfarin (i.e, COUMADIN, a blood thinner) Aminoglycosides (e.g., garamycin, gentamicin etc.) Phenytoin and carbamazepine (i.e., DILANTIN and TEGRETOL, anticonvulsants)