bruce wainman, phd. drugs and marketing drugs are often marketed as the most potent, the most...

Bruce Wainman, PhD

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

•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

Kinetics…

Drug Receptors

Drug binds to receptor, the rate of this occurrence is k1

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 k1 is slow and k-1 is fast.

The drug has a low affinity for this receptor.

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 k1

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 Kd

– i.e., k-1/k1 = Kd

– Kd is also called the dissociation constant– The reciprocal of Kd (i.e., (k1/k-1) is called affinity– Drugs with low Kd 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]

k1

k-1

[R] [X] [R X]k1 k-1. ..

=

[R] + [X] [RX]k1

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:

The neat thing about this is that if you take this formula ….[R] [X] [R X]k1 k-1

. ..=

[R] [X] [R X]k1 k-1. ..

=k1k1

[R] [X].=

[R X] k-1.

k1

Divide by k1

Almost there….

[R] [X].=

[R X] k-1.

k1

[R] [X].=

[R X]Kd

Substitute Kd for k-1/k1

.Divide both sides by [RX]

[R X] [R X]

Kd

[R] [X].=

[R X]

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.

=[R X] Kd

.

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

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

Log of Drug Concentration

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The Dose Response Curve

EC50

Log of Drug Concentration

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Equal in Efficacy and Full Agonists

Partial Agonist

50

EC50

EC50

?EC50

EC50

Affinity

• If the three drugs on the previous page differ in EC50

* and act at the same receptors then it is likely that they differ in affinity for the receptor.

* The EC50 is the concentration required to give half the maximal effect for that drug

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)

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.

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Agonist alone

Agonist plus

competitive antagonist

Agonist plus more

competitive antagonist

0

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?

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 wayAcetylcholine 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 KD = 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?

Log of Drug Concentration

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Agonist with increasing doses of antagonist

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Log of Drug Concentration

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Agonist with increasing doses of antagonist

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Agonist with a large dose of irreversible

antagonist or a noncompetitive

antagonist

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

Log of Drug Concentration

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50%Most potent Much Less

potent

Less potent

EC50

EC50

Log of Drug Concentration

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Much Less potent and lower

efficacy

Less potent but high efficacy

Most potent but lower efficacy

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.

Activity of Acyclovir(ZOVIRAX) Against Viral Growth

HSV 1 = herpes simplex virus Type 1, HCMV = human cytomegalovirus

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 ED50

Dose (mg)

Number

of

Responses 0

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

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.

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Sum

of

Responses

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.

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The Dose Response Curve- Quantal Effects

Log of Drug Dose0

50 ED50

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 ED50

Activity of Vincristine (ONCOVIN) Against Tumour Cell Lines

Cel

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)

What sort of dose/response curve is this?

Catharanthus roseus (Madagascar Periwinkle)

Dose (mg)

Activity of Morphine, Ibuprofen (ADVIL) and ASA (ASPIRIN) for Pain Control

What sort of dose-response curves are these?

•Fluoxetine = PROZAC•Amitriptyline = ELAVIL

Therapeutic Index and Therapeutic Window

Between a rock and a hard place….

Log of Drug Dose

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Dose-response curve for

therapeutic effect

Dose-response curve for toxicity

ED50

LD50

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Log of Drug Dose

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ED50

LD50

Dose-response curve for

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Dose-response curve for toxicity

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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.

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)