Therefore the drug with the lower K_d value shows greater receptor specificity.

.  A change of one log refers to a 10-fold change.  For example, a one-log increase in antibody titer could refer to an increase from 100 to 1000

10¹ à 10² (10 to 100).  A five-log increase from a value of ten can be expressed as

10¹ à 10⁶ (10 to 1,000,000).

sigmoidal (S-shaped)

a.    The bottom part of the S spans the range of doses that produce little or no response. 

b.    The straight part of the S, also known as the linear portion, spans the range of doses where an increase in dosage produces an increase in response.  When the slope of the linear portion is steep, a small increase in the dosage produces a large increase in the response. 

A steep slope coupled with an undesirable response means that there is a narrow therapeutic index for that drug.

c.    The top part of the S spans the range of doses where the maximal effect is achieved.  In this region, increasing the dosage does not produce an increase in the response.  

Potency describes the relationship between dose and the magnitude of the response that it produces. 

Potency is generally expressed as either the dose or concentration necessary to produce 50% of a drug’s maximal effect.  

When potency is expressed as a dose.

a dose that produces the desired effect in 50 per cent of a population.

When potency is expressed as a concentration (plasma)

a dose that produces the desired effect in 50 per cent of a population

occurred or didn't

"either or response"

A - highest potency & lowest efficacy

B>C>D - potency

B/C/D - same efficacy

N- has the lowest potency

L - greatest potency

M - lowest efficacy

L&N - same efficacy

Drug receptors can be binding sites for endogenous ligands or they can be enzymes.  Examples of drugs that bind to receptors specific for endogenous ligands include atropine (binds to muscarinic receptors), cimetidine (binds to H₂ receptors), and atenolol (binds to b₁ receptors).  Examples of drugs that bind to enzymes include enalapril (binds to angiotensin converting enzyme), lovastatin (binds to HMG CoA reductase), and indinavir (binds to HIV protease).

are capable of producing the maximal response for that cell or tissue when all of the active receptors are occupied.

When a drug binds to a receptor it activates the machinery of that cell, that same way a natural ligand does.

Same affinity for the receptor as the nautral ligand. The # of receptors determines which is more likely to bind. 

Ex: Narcan & morphine

Non-competitive (irreversible) antagonist

Irreversible antagonists generally bind to the receptor via a covalent bond. A covalent bond occurs when two molecules share an electron.  It is the strongest known bond and is less reversible than other bonds.

LDR shifts to the R, decreases potency

T_d50/Ed₅₀

The higher the therapeutic index the farther apart, more likely NOT to get toxic effect.

Drug B:Td50/Ed50 = 1,000/100 = 10 (thera index)

Drug A: Td50/Ed50 = 10/0.1 = 100 (thera index)

B is a safer drug than A. 

THERA INDEX NOT ALWAYS ACCURATE TO JUDGE SAFER DRUG

Mix of active/inactive isomers

With racemic mixture, more likely to have side effects.

Same chemical structures, different orientation.

Ex: Darvon & Novrad

One of a set of isomers whose molecules have the same atoms bonded to each other but differ in the way these atoms are arranged in space.

Darvon and Novrad are mirror images of each other. Consequently, they bind to different receptors and have different actions (darvon is an analgesic, novrad is an anti-tussive). They both are racemic mixtures of both drugs. 

Mirror image of sterioisomers

CHIRAL

an enantiomer is one of two stereoisomers that are mirror images of each other that are "non-superposable" (not identical), much as one's left and righthands are "the same" but opposite.

*agonist+competitive antagonist=curve shifts to the R.

*Can overcome competitive antag. with more agonist.

Agonist & competitive antagonist given:

-LDR curve shifts to the R so potency decreases.

-Need increased dose to achieve same efficacy

-If increased dose of agonist, will eventually take over agonist receptors

-most drugs dont irreversibly bind to receptors.

Same affinity for the receptor as the natural ligand. The # of molecules determines which is more likely to bind. 

Ex: narcan & morphine.

*competitive antag - decreases potency, shifts LDR to the R. Same efficacy, Just need more drug

*Non-competitive antag - shift curve to R & lowers, decreases potency & decreases efficacy.

1st line-agonist

2nd line-comp antag

4th line-non-comp. antag.

in this pict, have non-competitive irreversible antagonist. Have spare recepters. Get max response w/ only a few receptors.

means that sometimes we have more receptors present than are needed to produce a maximal effect.  The receptors that aren’t occupied when the maximal effect is achieved are considered to be "spare".

We can demonstrate the existence of spare receptors by administering an irreversible antagonist with an agonist and plotting the LDR for the agonist.  The agonist LDR curve that is obtained when the antagonist is co-administered will be parallel and to the right of the curve obtained when the agonist is given alone.  This means that a higher concentration of agonist is needed to produce the same response, because some of the receptors are occupied by the antagonist.  However, the height of the curve will be the same because the receptors that are not occupied by the antagonist are still in excess of the number needed to produce the maximal response.

 “spare”.

Let’s suppose that full agonist A occupies one receptor per mg of drug and the maximal effect is achieved when 10 mg of agonist A is given (hence 10 receptors are occupied).  If we give greater than 10 mg of agonist A, no further increase in response is produced.  Intuitively, we would think that this means that there are only 10 receptors to begin with.  After all, if we gave 15 mg, we would occupy 15 receptors and observe a greater response than when we gave 10 mg (and occupied 10 receptors).  We can show that this is not the case by first giving an irreversible antagonist.  Let’s suppose that 10 mg of irreversible antagonist B will occupy 10 receptors.  If we give irreversible antagonist B followed by agonist A, we would expect to observe no response, because all of the receptors are occupied.  However, this is not what we find.  When we give agonist A at a higher concentration, we can achieve the same response that we observed when we occupied 10 receptors (the maximal response).  This is because we have more than 10 receptors.  These additional receptors are the “spare receptors.” 

“the existence of spare receptors can be seen in many tissues and means that the K_d measured for an agonist will be higher than the EC₅₀ for the same ligand” (Kalant, 2000).  Let’s look at what this statement means.  You’ll remember that K_d is the plasma concentration of a drug (expressed as moles/liter) when 50% of the drug’s receptors are occupied.  EC₅₀ is the plasma concentration of drug necessary to produce 50% of the drug’s maximal effect.  If a drug’s EC₅₀ is less than its K_d, we know that the drug can produce 50% of its maximal effects while occupying less than 50% of its receptors.  To illustrate, consider a drug with an EC₅₀ value of 1 mole/liter and a K_d value of 2 moles/liter.  This drug can produce 50% of its maximal effect at a concentration that is one-half the concentration necessary to occupy 50% of the receptors.  This indicates that the number of receptors present exceeds the number needed to produce the maximal effect. 

refer to quantal responses, rather than graded responses.  This can be a bit confusing because the term “ED₅₀” is used to describe both graded and quantal effects.  The difference is that when ED₅₀ is used to describe graded effects, it refers to the dosage that produces 50% of a drug’s maximal effect.  When ED₅₀ is used to describe quantal effects, it refers to the dosage that produces the desired effect in 50% of patients.  You need to know how the response is measured in order to know whether ED₅₀ refers to quantal or graded responses.  However, when the term effective dose is used (not ED₅₀), it refers to quantal responses.  

The therapeutic index is the ratio of the TD₅₀ (the dose that produces a toxic effect in 50% of patients) to the ED₅₀ (the dose that produces a desired effect in 50% of patients).  The larger the gap between a drug’s TD₅₀ and its ED₅₀, the higher its therapeutic index.  When drugs are administered within their range of therapeutic doses, those that have a higher therapeutic index are less likely to produce toxic effects than those that have a lower therapeutic index.