Lec 1: Drug Receptors and Pharmacodynamics: Study Notes

Receptors and Pharmacodynamics: Key Concepts

Pharmacodynamics describes the actions of a drug on the body and how drug concentrations influence the magnitude of the response.
Therapeutic and toxic effects arise from interactions with receptors; receptors confer selectivity of drug action.
The molecular size, shape, and electrical charge of a drug determine whether it will bind to a receptor and with what affinity.
- The affinity of a receptor to a specific molecule will determine the concentration needed for this molecule to produce a response. The interaction between a drug and a receptor is specific.
Receptors are the primary targets for drug action; understanding receptor–drug interactions explains dose–response relationships and therapeutic windows.
Agonist: an agent that activates a receptor to produce a biologic effect.
- ENHANCES CELLULAR ACTIVITY
Antagonist: an agent that prevents the action of an agonist on a receptor, without producing an effect on its own.
- Antagonists:
  • Antagonists do not activate a signal generation.
  • Antagonists do NOT produce a reverse signal of the agonist.
  • Antagonists occupy the receptor and BLOCK the ability of an agonist to activate the receptor.
  - aka ZERO INTRINSIC ACTIVITY

Signal transduction (conceptual)

Drug binding to a receptor
generates signal transduction and elicits a biological response.
Second messengers or effector molecules
translate receptor binding into cellular responses

Receptors states:

exist in at least two states, inactive (R) and active (R*), in reversible equilibrium: R ⇄ R*.

Agonists shift the equilibrium toward R* to produce a biological effect.
Antagonists occupy the receptor but do not shift to R*; they block activation.
Partial agonists shift toward R* but yield a smaller fraction of receptors in the active state than a full agonist.
The magnitude of the biological effect is proportional to the fraction of receptors in the active state, R*.

Dose–response relationships and key metrics

The effect of a drug depends on its concentration at the receptor site, influenced by dose and pharmacokinetics (absorption, distribution, metabolism, elimination).
- Potency: usually represented by EC50; the concentration that produces 50% of the maximal response.
  - EC50= Concentration of drug that produces 50% of the maximal response = DETERMINES POTENCY
  - indicates the concentration needed to achieve half-maximal effect; lower EC50 means higher potency.
    1. EC50 is used to describe:
    a) the potency of the drug
    b) The efficacy of the drug
    c) The toxicity of the drug
    d) The affinity of the drug
    1. EC50 is:
    a) the concentration of drug that exerts 50% of the intrinsic activity
    b) the concentration of the drug that produces 70% of the intrinsic activity
    c) the concentration of the drug that produces 25 % of intrinsic activity
    d) the concentration of the drug that produces no intrinsic activity
Kd = Concentration of the drug that binds to 50% of the available receptors
- Used to determine the affinity of a drug for its receptor
- Kd 50 is used to describe:
  a) the potency of the drug
  b) The efficacy of the drug
  c) The toxicity of the drug
  d) The affinity of the drug
  - Kd: $K_d = \frac{[D][R]}{[DR]}.$
  - Kd = dissociation constant of D-R complex; it quantifies the affinity of the drug (D) for the receptor (R), where a lower Kd indicates a higher affinity, higher Kd indicates weaker interaction.
    - Higher affinity (lower Kd) generally yields greater receptor occupancy at a given concentration.
  - Receptor–drug complex: [DR], free receptor [R], free drug [D], total receptors = [R] + [DR].
Dose–response relationships are often plotted as a hyperbola or logarithmically; curves can be used to determine potencies and compare efficacies.
Fraction of receptors bound at a given drug concentration (occupancy) for a simple 1:1 interaction
Intrinsic activity (IA) refers to the ability of a bound ligand to activate the receptor.
- Efficacy: represented by Emax; the maximal effect achievable by the drug.
  - Efficacy (Emax) is the maximal response achievable with a drug; it reflects the ability to activate receptors and produce a cellular response.
  - As receptor occupancy increases, the pharmacologic effect rises until all receptors are occupied (Emax).
- Full agonist: binds to receptor and produces a maximal biologic response equivalent to the endogenous ligand.
  - Example: Phenylephrine as a full agonist at α1-adrenoceptors, producing the same Emax as norepinephrine (NE) in causing vasoconstriction.
    - ALL FULL AGONISTS FOR A RECEPTOR POPULATION SHOULD PRODUCE THE SAME EMAX
- Partial agonist: binds and activates but yields a maximal response less than a full agonist even when all receptors are occupied.
  - Partial agonists may have higher, lower, or equal affinity compared to full agonists.
  - EVEN IF ALL RECEPTORS ARE OCCUPIED, PARTIAL AGONISTS CANNOT PRODUCE THE SAME EMAX AS A FULL AGONIST
Spare receptors: a subset of receptors exist in excess; full maximal effect can be achieved without occupying all receptors.

Inverse agonist: produces the opposite pharmacologic effect of an agonist when binding to the receptor.

Competitive and non-competitive antagonism; allosteric modulation

Antagonists bind receptors without activating them; they block the action of agonists.
Competitive antagonists (reversible): bind the same site as the agonist; can be overcome by increasing agonist concentration; shift the dose–response curve to the right without changing the maximum effect (Emax).
- can shift agonist dose response curve TO THE RIGHT (INCREASED EC50 WITHOUT AFFECTING EMAX)
- BIND SAME RECEPTOR
Non-competitive antagonists: bind to a site other than the agonist binding site (allosteric or irreversible binding); reduce the maximum effect (Emax) and cannot be overcome by simply increasing the agonist concentration; may be allosteric activators or inhibitors.
- can shift EMAX DOWNWARDS, with NO SHIFT OF EC50 VALUES
- BIND DIFFERENT RECEPTOR
  - Allosteric site: a binding site distinct from the active site where allosteric modulators (activators or inhibitors) bind to modulate receptor activity.
  - Allosteric modulator: binds at a site other than the active site and modulates receptor activity as an activator/inhibitor

Receptors can be classified into four major transmembrane/ intracellular classes, plus ligand-gated/voltage-gated ion channels:

1) Intracellular receptors (cytoplasm or nucleus); ligands are lipophilic (e.g., steroids, thyroid hormone).

Intracellular ligands: steroids, thyroid hormones; ligands diffuse through the membrane to reach intracellular receptors because they are lipid soluble
2) Transmembrane enzyme-linked receptors with extracellular ligand-binding domain and cytosolic catalytic domain (often tyrosine kinase).
3) Transmembrane tyrosine kinase receptors (a subset of enzyme-linked receptors).

most abundant
4) G protein-coupled receptors (GPCRs); activate heterotrimeric G proteins.

GPCRs couple to heterotrimeric G proteins composed of α, β, and γ subunits.

The Gα subunits (Gs, Gi, Gq) regulate downstream effectors:
- Gs activates adenylyl cyclase (AC) → increases cAMP → activates PKA.
- Gi inhibits adenylyl cyclase → decreases cAMP.
- Gq activates phospholipase C (PLC) → cleaves PIP2 into IP3 and DAG; IP3 increases Ca2+, DAG activates PKC.
  - When a G-protein coupled receptor (GPCR) binds to its ligand, the following sequence of events occurs:
    - The ligand binds to the extracellular side of the GPCR.
    - This induces a conformational change in the GPCR.
    - The GPCR acts as a guanine nucleotide exchange factor (GEF) for the G-protein.
    - The Gα subunit of the heterotrimeric G-protein exchanges GDP for GTP.
    - This exchange causes the Gα subunit to dissociate from the βγ subunits and the receptor.
    - The active Gα-GTP and the βγ dimer can then go on to activate downstream signaling pathways.
Once a G-protein coupled receptor (GPCR) has bound to its ligand, which of the following steps
allows the α subunit to dissociate from the receptor and trigger downstream cascades?
a. Exchanging the G-protein’s bound GDP for a GTP
b. Exchanging the G-protein bound ADP for an ATP
c. Exchanging the G-protein association with a magnesium ion for a calcium ion
d. Degradation of the GPCR’s C-termina tail that is bound too the α subunit
5) Ion channels: two primary types
Ligand-gated ion channels open in response to ligand binding.
Voltage-gated ion channels open in response to changes in membrane potential.

Receptor regulation: desensitization, tachyphylaxis, down/up-regulation, and tolerance

Tachyphylaxis: diminished response to repeated agonist exposure; an acute reduction in response.
Desensitization: receptor becomes less responsive after repeated stimulation.
Down-regulation: receptors are sequestered away from the cell surface and become unavailable; may be recycled (up-regulation) or degraded (down-regulation).
Up-regulation: increase in receptor number on the cell surface via recycling of receptors, restoring sensitivity.
Antagonist-induced up-regulation: repeated antagonist exposure can increase receptor reserves on the surface.
- During this recovery phase, unresponsive receptors are said to be “refractory.”
  • Repeated exposure of a receptor to an antagonist may result in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the total number of receptors available
Tolerance: a gradual decrease in response requiring higher doses to achieve the same effect; develops over a longer period and can sometimes be overcome by increasing dose, unlike tachyphylaxis.