8/25 5221 DR Curves, Therapeutic Index

How to determine the relationship between the administered dose of a drug and the biological response

This is done using a dose-response curve

• Most relationships in a biological system are hyperbolic with increasing concentration

• Use the logarithm of the dose concentration to generate a sigmoidal curve

Sigmodal curve is preferable because:

1. Accommodates a wider range in drug dose

2. Maximal response plateau is more defined

Define affinity

How strongly a drug binds to its receptor

• Measure of the interaction strength between a drug and the receptor binding site

Refers to chemical forces that cause a substance to bind to its receptor

A drug that binds strongly and/or rapidly has high _

affinity

Drugs with higher affinity tend to exert a greater/longer-lasting effect

Define efficacy

A drug’s ability to activate the receptor once bound

The maximum effect that a drug can produce, regardless of dose

• Drugs with higher efficacy generally produce greater effects

• 100% efficacy = max possible response

Efficacy is not the same as affinity

A drug with high affinity does not always have high efficacy

E.g., an antagonist may bind with high affinity but have no efficacy

• I.e., strongly bound but not response

• Antagonists don’t exert an effect on receptors, they just block them

E.g., partial agonist: can be strongly bound, but produces only a small response

Define potency

The drug concentration needed to produce a defined amount of max response (usually 50%)

A more potent drug requires a lower concentration to produce the specified percentage response (more left)

Potency is an indication of the:

1. Drug’s affinity for the receptor

2. Number of receptors

3. Ability of drug/receptor complex to initiate downstream signaling events

Potency is unrelated to maximal effect (efficacy)

A potent drug is not always the most efficacious

Dose-response curves can be steeper or shallower than a normal curve

Steep curve has higher slope factor

Shallow curve has lower slope factor

Slope is Important in the safety of the administration of the drug to the patient (Therapeutic Index)

Steep slope

Small changes in concentration have big effect

• Individualization of dosage is now important

Shallow slope

Small changes in concentration have little effect

• The standard dose can be administered to most patients

Selectivity

How selective a drug is for a receptor/subtype is important

• Drugs may act preferentially on a receptor (e.g., β-adrenergic receptor) or subtype (e.g., β1 vs β2)

E.g., Salbutamol is ~10x more effective in stimulating β1–adrenoreceptors in the airway smooth muscle than β2–adrenoreceptors in the heart

• Has selectivity for action at β1–adrenoreceptor

Effectiveness differs from efficacy as it also considers how well a drug works in the real world

A drug may have high efficacy but low effectiveness due to side effects that limit use

Efficacy vs Potency

Clinically, efficacy is more important than potency and is a major determinant of a drug’s effectiveness

Can increase the dose of less potent drug to obtain the same effect of more potent one

Potency more significant regarding toxic side effects of a drug

e.g., 500 mg of acetaminophen and 200 mg of ibuprofen usually resolve a headache

When judging relative merits of a drug consider many factors including side effects, potential toxicity, duration of effect, and cost