L 6-7 Receptor Theory, Dose Response, and Genetic Considerations

Receptor Theory, Dose Response, and Genetic Considerations

Learning Objectives

Upon completion, students will be able to:

• Define Agonists and Antagonists: Understand drugs that activate or block receptors.

• Compare Inhibitors: Differentiate between competitive, noncompetitive, and uncompetitive inhibitors, and allosteric binding.

• Define Key Pharmacological Terms: Understand $ext{K}<em>d$, $ext{EC}</em>{50}$, $ext{ED}<em>{50}$, $ext{LD}</em>{50}$, potency, efficacy, coupling, spare receptors, therapeutic index, and therapeutic window.

• Interpret Dose-Response Graphs: Read and interpret potency, efficacy, and quantal dose-response graphs.

• Define Synergism and Antagonism: Understand combined drug effects and interpret an isobologram.

• Calculate Doses: Compute dose rates, maintenance, and loading doses.

• Correlate Dosing: Relate dosing intervals and half-lives to drug plots.

• Explain Dosing Regimens: Understand the need for personalized dosing due to patient variability.

• Explain Receptor Binding to Drug Effects: Clarify how receptor binding leads to drug effects, including $ext{K}_d$ and the concept of spare receptors.

• Describe Transmembrane Signaling: Outline basic mechanisms of transmembrane signaling and provide examples of each type.

• Describe G Protein Signaling: Detail the signaling cascades involving G proteins and common second messengers.

• Describe Autophagy and Apoptosis: Explain these cellular processes.

Pharmacokinetics vs. Pharmacodynamics

• Pharmacokinetics: What the body does to the drug (Absorption, Distribution, Metabolism, Excretion - ADME).

• Pharmacodynamics: What the drug does to the body (its effects and mechanisms of action).

Dosing Principles

• Timing of Drug Effect: The amount of available drug depends on ADME. The drug's effect is influenced by ADME, dosing strategies related to drug half-life, and the drug's mechanism and duration of activity.

• Key Terms for Drug Effects:

  • $ext{C}_p$: Plasma concentration.

  • Minimum Effective Concentration (MEC): The threshold concentration required for a desired activity or an adverse (toxic) activity.

• Impact of Pharmacokinetics on Drug Curves:

  • Dosing route significantly impacts absorption.

  • Clearance is crucial for predicting elimination; it is a function of liver and kidney activity.

  • Genetic differences in metabolizing enzymes can alter clearance.

• Half-Life ($T_{1/2}$) and Repeat Dosing:

  • Half-life: The time it takes for half of the drug to be cleared from the body.

  • Formula: $T<em>{1/2} = rac{(0.693 imes V</em>d)}{CL_p}$

    • $ext{V}_d$: Volume of distribution.

    • $ext{CL}_p$: Clearance from plasma.

  • Goal: To consistently maintain drug levels within the therapeutic window.

  • Steady State: Dosing every half-life typically leads to a steady state in 4-5 half-lives. The same principle applies when changing to a new dose.

  • Example (4-hour half-life): If $10 ext{ mg}$ is given every 4 hours (one half-life), the cumulative amount of drug reaches an approximate steady state of $20 ext{ mg}$ around $28-32$ hours (7-8 half-lives).

• Dosing Calculations:

  • Dosing Rate: The rate at which the drug needs to be administered.

    • Formula: $ext{Dosing Rate} = rac{( ext{Clearance (CL)} imes ext{Target Concentration (TC)})}{ ext{Bioavailability (F)}}$

    • For intravenous (IV) administration, $F=1$. Example for Theophylline ($ext{CL} = 2.8 ext{ L/h/70kg}$, $ext{TC} = 10 ext{ mg/L}$): $ext{Dosing Rate} = rac{(2.8 ext{ L/h/70kg} imes 10 ext{ mg/L})}{1} = 28 ext{ mg/h/70 kg}$ (assuming IV).

  • Maintenance Dose: The dose given to maintain steady-state concentration.

    • Formula: $ext{Maintenance Dose} = rac{( ext{Dosing Rate})}{F} imes ext{Dosing Interval}$

    • Example for Theophylline ($ext{Oral F} = 0.96$): A $28 ext{ mg/h}$ dosing rate would result in:

      • 8-hour interval: $rac{28 ext{ mg/h}}{0.96} imes 8 ext{ hours} hickapprox 233 ext{ mg/dose}$

      • 12-hour interval: $rac{28 ext{ mg/h}}{0.96} imes 12 ext{ hours} hickapprox 350 ext{ mg/dose}$

      • 24-hour interval: $rac{28 ext{ mg/h}}{0.96} imes 24 ext{ hours} hickapprox 700 ext{ mg/dose}$

  • Dosing Interval and Peaks/Troughs: Adjusting the dosing interval affects the plasma concentration peaks and troughs, ideally keeping them within the therapeutic window.

  • Loading Doses: Administered to rapidly achieve a target concentration (and thus therapeutic effect) before steady state is reached by maintenance doses.

    • Formula: $ext{Loading Dose} = rac{( ext{Volume of Distribution (V}_d ext{)} imes ext{Target Concentration (TC)})}{F}$

    • For intravenous (IV) administration, $F=1$. Example for Theophylline ($ext{V}_d = 35 ext{ L}$, $ext{TC} = 10 ext{ mg/L}$): $ext{Loading Dose} = rac{(35 ext{ L} imes 10 ext{ mg/L})}{1} = 350 ext{ mg}$ (assuming IV).

    • Example: Tetracycline with a $T_{1/2} = 8$ hours might use a $500 ext{ mg}$ loading dose followed by $250 ext{ mg}$ every 8 hours.

Drug Efficacy and Toxicity

• Dose-Response Curve: Plots drug effect against drug concentration (often on a log scale for concentration).

  • $ext{EC}_{50}$: The effective concentration of a drug that produces 50% of the maximal response.

• Potency vs. Efficacy:

  • Potency: How much drug is required to produce a specific effect (e.g., its $ext{EC}_{50}$).

  • Efficacy: The maximum effect a drug can produce (the height of its dose-response curve).

  • Drugs with lower $ext{EC}_{50}$ are more potent. Drugs reaching a higher maximal effect are more efficacious.

  • Example from graph: Ranking drugs by potency (most to least) involves comparing their $ext{EC}_{50}$ values (left-shifted curve is more potent). Ranking by efficacy (most to least) involves comparing their maximal effect (higher plateau is more efficacious). Drugs with steep curves (like 'D' in some examples) require careful consideration.

• Balancing Efficacy and Toxicity in Humans:

  • The goal is to administer enough drug for desired effects without causing unacceptable toxicity.

  • Preclinical studies: Determine doses that are toxic or lethal (e.g., $ext{LD}_{50}$).

  • Human clinical trials: Establish well-tolerated and effective doses, leading to definitions of key drug thresholds.

• Quantal Dose-Response Relationships: Describe the effects of varying doses on a population.

  • $ext{ED}_{50}$: The dose at which 50% of subjects in a population show a therapeutic effect (a clinical outcome).

  • $ext{TD}_{50}$: The dose at which 50% of subjects show a particular toxic effect.

  • $ext{LD}_{50}$: The dose that is lethal to 50% of animals receiving it (from preclinical data).

  • Note: $ext{ED}<em>{50}$ (clinical result) differs from $ext{EC}</em>{50}$ (activity at receptor).

• Therapeutic Index (TI) and Therapeutic Window:

  • Therapeutic Index: A ratio derived from preclinical (animal) studies, indicating drug safety.

    • Formula: $ext{TI} = rac{LD<em>{50}}{ED</em>{50}}$ or $ext{TI} = rac{TD<em>{50}}{ED</em>{50}}$

    • Example: If $ext{LD}<em>{50} = 120 ext{ mg}$ and $ext{ED}</em>{50} = 4 ext{ mg}$, then $ext{TI} = rac{120 ext{ mg}}{4 ext{ mg}} = 30$.

  • Therapeutic Window: The range of doses (or plasma concentrations) in human patients that is likely to produce desired effects while minimizing toxicity. This is the practical equivalent of TI for humans.

Drug Interactions (Additivity, Antagonism, Synergism)

• Combining Drugs: Can result in additive, antagonistic, or synergistic effects, which can be visualized using an isobologram.

  • Additive: The combined effect is equal to the sum of individual effects. The doses of each drug that achieve a specific effect (e.g., $ext{EC}_{50}$) lie along a diagonal on an isobologram.

  • Antagonism: The combined effect is weaker than expected. The effective dose combination falls outside the additive line on an isobologram.

  • Synergism: The combined effect is stronger than expected, allowing for lower doses of each drug to achieve the desired effect. The effective dose combination falls inside the additive line on an isobologram.

Drug Response and Receptor Interactions

• Receptor Binding: Drugs bind to receptors via various chemical bonds:

  • Covalent bonds: Very strong, often irreversible under biological conditions.

  • Electrostatic bonds: More common. Include relatively strong ionic linkages (between charged molecules), weaker hydrogen bonds, and very weak partial dipole interactions.

  • Hydrophobic bonds: Weak, important for lipid-soluble drugs interacting with cell membranes or internal receptor pockets.

  • Van der Waals forces: Weak, short-range electrostatic attractive forces between uncharged molecules, arising from transient electric dipole moments.

• Agonism and Antagonism at Receptors:

  • Receptors exist in an active ($ext{R}<em>a$) or inactive ($ext{R}</em>i$) state, with potential basal constitutive activity.

  • Agonists: Drugs that bind to a receptor and produce a response, usually by stabilizing the $ext{R}<em>a$ state (increasing the $ext{R}</em>a$:$ext{R}_i$ ratio).

    • Full agonists: Can maximize the receptor's response.

    • Partial agonists: Produce a lower maximal effect than full agonists, even at saturating concentrations. They have affinity and intrinsic activity but do not fully stabilize the $ext{R}_a$ state. (e.g., Buprenorphine is a weak partial agonist of $ext{µ}$ opioid receptors, morphine is stronger, fentanyl is a full agonist.) Partial agonists can also compete with endogenous full agonists to reduce response.

  • Antagonists: Prevent agonists (or inverse agonists) from binding and altering the $ext{R}<em>a$:$ext{R}</em>i$ ratio, thus preventing activity above or below constitutive levels if present.

  • Inverse agonists: Bind to the receptor and stabilize the $ext{R}<em>i$ state (reducing the $ext{R}</em>a$:$ext{R}_i$ ratio), thereby reducing activity below basal constitutive levels.

• Competitive vs. Non-Competitive Inhibitors:

  • Competitive inhibitors: Bind reversibly to the same active site as the agonist, actively competing. Increasing agonist concentration can overcome the inhibition.

    • Effect on Dose-Response Curve: Shifts the curve to the right (decreases apparent potency), but the maximal effect (efficacy) remains the same.

  • Non-competitive inhibitors: Bind to a different site or bind irreversibly/pseudo-irreversibly to the active site, preventing agonist binding or effect, regardless of agonist concentration.

    • Effect on Dose-Response Curve: Flattens the curve (decreases efficacy/maximal response), and may also shift it to the right.

• Activity of Allosteric Binders:

  • Allosteric inhibitors: Bind to a site distinct from the agonist-binding site, decreasing the receptor's affinity or efficacy for the agonist.

    • Effect on Dose-Response Curve: Shifts curve down and/or right (decreases efficacy and/or potency).

  • Allosteric activators: Bind to a distinct site, increasing the receptor's affinity or efficacy for the agonist.

    • Effect on Dose-Response Curve: Shifts curve up and/or left (increases efficacy and/or potency).

• Uncompetitive Inhibitors (for Enzymes):

  • A special type of inhibition where the inhibitor only binds to the enzyme-substrate (ES) complex, not to the free enzyme or substrate. It prevents the release of the product, effectively