Chapter 2: Drug Receptors & Pharmacodynamics

Define a drug receptor

- Specific target molecule that the drug molecule interacts with that plays a regulatory role in the biologic system.

- Most drug receptors are proteins

List and describe the major types of protein drug receptors.

- Regulatory proteins (mediate the activities of endogenous molecules such as neurotransmitters, hormones, and signaling molecules)

- Enzymes (mostly inhibition by binding a drug)

- Transport proteins (move ions, neurotransmitters, and other molecules across plasma membrane)

- Structural proteins (maintain cell shape or form, and some drugs target them to disrupt structure or function)

List the key components of pharmacodynamics including receptors/effectors, dose-response relationships, agonists and antagonists, signaling mechanisms, and receptor regulation.

1. Receptors / Effectors

• Receptors: Proteins drugs bind to in order to produce an effect

• Effectors: Ion channels, enzymes, or proteins that cause the cell’s response

• Drug binding → receptor activation → effector response

2. Dose–Response Relationships

• Shows how drug dose relates to effect

• Efficacy (Emax): Maximum effect a drug can produce

• Potency (EC50): Dose needed to produce 50% of max effect

• Higher potency ≠ greater efficacy

3. Agonists

• Full agonist: Produces maximum response

• Partial agonist: Produces less than max, even at high dose

• Inverse agonist: Produces opposite effect of agonist

• Bind receptor and activate it

4. Antagonists

• Competitive: an antagonist that can be overcome by increasing the concentration of agonist (active site binding) (effect reduced by more agonist)

• Noncompetitive: an antagonist that cannot be overcome by increasing agonist/endogenous ligand concentration (max effect reduced)

  • 1. Active site binding (irreversible through covalent bond)

  • 2. Allosteric site (reversible through noncovalent interactions (mostly) or irreversible through covalent bond)

• Bind receptor but do not activate it

5. Signaling Mechanisms

• Intracellular lipid-Soluble Drug

• Ligand-Regulated Transmembrane Enzymes (including receptor tyrosine kinases)

• Cytokine Receptors (associated with separate kinases)

• Ion Channels

• G Proteins and Second Messengers

6. Receptor Regulation

• Receptors can be dynamically regulated in number, location, and interaction with other molecules (but not always.

  o   As a result of continuous exposure to agonists:

  §  1. Loss of the receptor response upon frequent exposure (tachyphylaxis or tolerance or desensitization)

  §  2. Loss in receptor number (downregulation)

  o   As a result of continuous exposure to antagonist:

  §  1. Upregulation in receptor number (upregulation)

Explain how drug receptors determine quantitative relationships between drug dose and pharmacologic effects.

- Receptors determine quantitative relations between drug dose and pharmacologic effects (receptors affinity for binding a drug determines the concentration of drug required to form significant drug-receptor complexes)

Receptor affinity describes how tightly a drug binds to

its receptor.

– High affinity → the drug binds easily and tightly

– Low affinity → the drug binds weakly

- Basically receptors control how much drug is needed to produce an effect

Explain how receptor selectivity contributes to selective drug action and its clinical relevance.

- Receptors are responsible for selectivity of drug action (so to respond to specific signal and not meaningless ones) (physio-chemical nature of drug determines binding ability to a specific receptor)

- Selectivity refers to the ability of a drug to bind preferentially to one receptor over another

Clinical Relevance:

- Maximizes Therapeutic Effect: Targets the specific pathway needed to treat a disease.

- Minimizes Side Effects: Fewer unwanted effects occur because the drug does not bind to receptors in other, non-targeted tissues.

In short: Higher selectivity = Higher efficacy + Lower side effects. 

Explain how receptors mediate the actions of agonists, antagonists, and allosteric modulators.

- Receptors mediate the actions of pharmacologic agonists and antagonists, and allosteric modulators by binding, which either activate, block, or modify receptor activity to regulate the biological response.

Agonist

- Binds to receptor and activates the receptor, which directly or indirectly brings about the effect

Antagonist

- Bind to receptors but do not activate them

- Primary action is to reduce the effects of agonists that normally activate receptors (i.e., other drugs or endogenous ligands)

Allosteric modulators and their role in regulating receptor activity

- Allosteric modulators: bind to a site separate from the endogenous ligand

Two types:

- Positive am: activate receptor activity

- Negative am: inhibit receptor activity

Summarize the conformational changes that occur in a receptor after agonist binding.

- Conformational change in the receptor protein that shifts it from an inactive to an active state. This change allows the receptor to interact with downstream signaling molecules (like G proteins or ion channels), initiating a cascade of events that produces a pharmacologic response.

- Full agonists produce a strong conformational shift and maximal response

- Partial agonists induce a smaller shift, resulting in only a partial response.

PNEUMONIC: agonist binding → receptor changes shape → receptor activates downstream effectors → pharmacologic response occurs

Describe the concept of potency in pharmacology

- Potency: concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect

- Basically how much drug is needed to produce an effect (usually measured by EC₅₀ or ED₅₀).

Explain the concept of maximal efficacy in pharmacology

- Maximal Efficacy (or Efficacy): the largest effect that can be achieved with a particular drug

Define therapeutic window

- The safest range between the minimum therapeutic concentration and the minimum toxic concentration of a drug.

- Basically the safe dose range where a drug is effective without being toxic.

Summarize the role of transmembrane signaling in drug action

- Drugs act by binding to transmembrane receptors, which transmit signals inside the cell through protein families and second messengers to produce a response.

List the five basic mechanisms of transmembrane signaling through which drugs act

- Intracellular Lipid-Soluble Drug

- Ligand-Regulated Transmembrane Enzymes (including receptor tyrosine kinases)

- Cytokine Receptors (associated with separate kinases)

- Ion Channels

- G Proteins and Second Messengers