Pharmacology Lecture 2: Agonists & Dose-Response Curves

Strand 1: General Principles of Pharmacology - Lecture 2: Agonists and Dose-Response Curves

• Agonists are ligands (drugs, hormones, or neurotransmitters) that bind to receptors to elicit a cellular response.
• Dose-response curves are semi-logarithmic plots comparing agonist concentration to the resulting response.
• Dose-response curves reveal potency and efficacy of drugs.
• Potency refers to the amount of drug needed to produce a specific response. Lower EC50 values indicate higher potency.
• Efficacy describes the ability of an agonist to activate a receptor and produce a response. It's the maximum possible effect an agonist can produce.
• Full agonists produce the maximal response; partial agonists produce less than maximal responses. Inverse agonists produce the opposite effect of the agonist.
• Dose is extremely important due to the poisonous qualities of many compounds. The dose dictates whether a substance is beneficial or hazardous.
• Graded dose-response curves describe the response of a particular biological system (e.g., isolated tissue, animal, patient) to varying agonist concentrations. The response is measured against agonist concentrations.
• Quantal dose-response curves describe the drug doses needed to elicit a specified response within a population.
• The logarithmic axis on a dose-response graph represents a 10-fold increase in concentration for each unit.
• Affinity is the strength with which an agonist binds to a receptor; it's described by the dissociation constant (Kd). A lower Kd value indicates higher affinity.
• A high affinity drug binds to the receptor more readily than it dissociates (k1 > k-1).
• Receptor saturation (Bmax), the maximum number of binding sites, is easily measured, but measuring affinity (Kd) is harder.

Agonist or Antagonist?

• Naloxone is an antagonist that blocks opioid receptors, while morphine is an agonist that activates them.

Learning Outcomes

• To understand drug potency and efficacy based on dose-response curves.
• To distinguish competitive from non-competitive antagonism.
• To understand graded and quantal dose-response curves.
• To define affinity and receptor-binding curves and discuss how to use them.
• To compare potency and efficacy from dose-response curves.
• To understand full, partial, and inverse agonists.

Agonist Mechanism

• A ligand (drug, hormone, or neurotransmitter) binds to a receptor, leading to an agonist-receptor complex. This complex induces a cellular response.
• Salbutamol (example) binds to a β2-adrenoceptor, causing an increase in cAMP and resulting in bronchodilation.

Two-State Hypothesis

• Describes the occupancy and activation of a receptor by an agonist through reversible interactions.
• A receptor exists in two states: rested (R) and activated (R*).
• K1 is the rate of association of the agonist with the receptor; K-1 is the rate of dissociation of the agonist receptor complex.

Key Concepts Summary

• A key concept to understand the different types of agonists.
• Dose response plots of differing drugs are key to understanding the clinical effects for a particular drug.

Affinity Summary

• Affinity is the tendency of a ligand to form a stable complex with a receptor.
• Affinity is determined by the strength of the interactions (number and type of bonds) between the ligand and receptor
• Affinity is characterized by the dissociation constant (Kd).

Potency

• Potent drugs elicit a response at low concentrations.
• Potency depends on the drug's affinity and receptor density.

Receptor Reserves

• Systems with spare receptors can exhibit signal amplification.
• Many receptors need to be occupied to elicit a maximal response.

Efficacy

• Efficacy describes the ability of an agonist to activate a receptor.
• It's the maximum effect the agonist can produce, regardless of the dose.
• Full agonists produce the maximum effect. Partial agonists produce a submaximal effect.

Inverse Agonists

• Inverse agonists have higher affinity for the inactive receptor state (unoccupied).
• They produce the opposite effect of the usual agonist.

Allosteric Modulators

• These are molecules that bind to a receptor in a location separate from the agonist binding site.
• They modify the receptor's response to agonist binding, either increasing or decreasing it.
• The can be positive allosteric modulators or negative allosteric modulators, effecting the agonist's efficacy.

Desensitization of Receptors

• The drug's effect decreases over time due to repeated administration
• This is termed tachyphylaxis.
• Contributing factors may include receptor conformational changes, internalization, depletion of mediators, alterations in drug metabolism & homeostasis.