Pharmacodynamics 2

What is receptor theory?

• Receptor theory states that drugs exert their effects by binding to specific receptors, and that receptors determine the relationship between drug dose and pharmacologic effect, as well as drug selectivity

• Receptors explain why drugs are selective and why dose matters

How was the existence of receptors first inferred?

From observations of chemical and physiological specificity of drug effects before receptors were physically identified

What roles do receptors play in pharmacology?

• Determine dose–response relationships

• Mediate effects of agonists and antagonists

• Are responsible for selectivity of drug action

What are the major types of drug receptors?

• Regulatory proteins

• Enzymes

• Structural proteins

What are regulatory protein receptors?

• Cell-surface or intracellular proteins that mediate effects of endogenous signaling molecules

• Examples: Dopamine receptors, acetylcholine receptors, steroid hormone receptors

How do enzymes act as drug receptors?

• Drugs can inhibit (or rarely activate) enzymes, reducing their activity

• Examples: antibiotics inhibiting bacterial enzymes

What are structural protein receptors?

• Proteins involved in cell structure that drugs bind to and inhibit

• Examples:

• Tubulin → receptor for colchicine (anti-inflammatory)

• Taxol binds tubulin (anticancer)

What is a chemical antagonist?

• A drug that binds directly to another drug, inactivating it

• Example: Protamine binds heparin, neutralizing its anticoagulant effect

What is a physiological antagonist?

• Two drugs produce opposing effects through different pathways or receptors

• Example: Insulin counteracts hyperglycemia caused by glucocorticoids

What is a pharmacological antagonist?

A drug that binds to a receptor but does not activate it, thereby blocking agonist effects

What is a non-competitive antagonist?

• An antagonist that binds:

• Irreversibly

• At a different site than the agonist

• Increasing agonist concentration cannot overcome inhibition

How do irreversible antagonists affect drug response?

They permanently reduce the number of functional receptors, lowering maximum response (Emax)

How do competitive antagonists differ from non-competitive antagonists?

• Competitive antagonists can be overcome by ↑ agonist

• Non-competitive antagonists cannot

What is an agonist?

A drug that binds a receptor and activates it, producing a biological response

What is a full agonist?

Produces maximum receptor activation and maximal effect

What is a partial agonist?

• Binds the same receptor as a full agonist but produces a lower maximal effect, even at full receptor occupancy

• Partial agonists have lower efficacy, not lower affinity

Why do partial agonists have lower efficacy?

They bind the receptor but do not promote the same conformational change, often stabilizing the inactive form

How can a partial agonist act as an antagonist?

In the presence of a full agonist, it competes for binding and reduces overall effect

What determines drug potency?

How tightly a drug binds its receptor (affinity) → measured by EC50

What determines drug efficacy?

• The maximum effect (Emax) the drug can produce

• Potency ≠ efficacy

What are spare receptors?

Receptors are “spare” when maximum response occurs without full receptor occupancy

How do spare receptors affect dose–response curves?

They shift the curve left, making the drug appear more potent

How are spare receptors demonstrated experimentally?

By using irreversible antagonists and showing maximal response is still achievable

What is coupling efficiency?

How efficiently receptor binding is translated into a cellular response

What is a quantal dose–response curve?

• Measures the percentage of a population that responds to a drug dose

• Used for: ED50, TD50, LD50

What does a steep dose–response curve indicate?

Small changes in dose lead to large changes in effect, increasing risk of toxicity

Why do patients respond differently to the same drug?

• Differences in pharmacokinetics

• Differences in receptor number

• Differences in post-receptor signaling

What is the most important cause of variability in drug response?

Post-receptor functional differences

How do β-blockers relate to receptor number?

Chronic use can decrease receptor number, altering response

Are drugs specific or selective?

Drugs are selective, not specific

Why do drugs cause side effects?

• Binding to multiple receptors

• Same receptor present in different tissues

How can drug benefit and toxicity be related?

1. Same mechanism, different dose

2. Same mechanism, different tissue

3. Different receptors entirely