Introduction to Pharmacodynamics

Pharmacology: The study of chemical actions on biological systems.
- Medical Pharmacology: Concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease.
- Toxicology: Focus on undesirable effects of chemicals on biological systems.

Pharmacokinetics (PK): Describes the effects of the body on drugs (Absorption, Distribution, Metabolism, Excretion - ADME).
Pharmacodynamics (PD): Denotes the actions of the drug on the body (mechanism of action, therapeutic and toxic effects).
Conceptual distinction:
- What the body does to the drug (PK) vs. What the drug does to the body (PD).

Pharmacodynamics (PD): The study of the biochemical and physiological effects of drugs and their mechanisms of action.

Receptors: Specific molecules in a biological system with which drugs interact to produce changes in function. Receptor binding translates into pharmacologic effect.
- In mathematical terms, a “receptor” is any binding site for a drug on a biological macromolecule (enzyme, ion channel, transporter, structural protein, or DNA).
- The more modern term "drug targets" is broader and encompasses receptors as a subclass of drug targets, specifically those proteins that bind ligands and transduce signals.

Effectors: Molecules that translate the drug-receptor interaction into changes in cellular activity.
- Example:
- Albuterol (Drug): Binds to $β_2$-adrenergic receptor (Receptor) → activates adenylyl cyclase (Effector) → increases $cAMP$ (Second messenger) → activates PKA (Effector) → Physiological effect (smooth muscle relaxation leading to bronchodilation).

By Binding Site
- Orthosteric: Binds at the natural ligand site (e.g., albuterol at $β_2$ receptor).
- Allosteric: Binds to a different site, modulating receptor function (e.g., benzodiazepines at GABA$_A$ receptor).
By Functional Effect
- Agonist: Activates receptor → produces effect; includes full vs. partial agonists.
- Antagonist: Binds but does not activate → blocks agonist; classified as competitive vs. non-competitive.
By Mode of Modulation
- Activator: Increases activity of target (e.g., allosteric activators).
- Inhibitor: Decreases activity of target (e.g., enzyme inhibitors).
By Chemical Interaction
- Non-covalent (reversible): Hydrogen bonds, ionic, hydrophobic forces (most drugs).
- Covalent (irreversible): Permanent bonds leading to long duration (e.g., aspirin).

Agonist: Binds to the active site and activates the receptor; examples include albuterol ($β_2$ agonist) for asthma.
Antagonist: Binds to the receptor and blocks agonist-mediated activation; example is metoprolol (β1-receptor blocker) for cardiovascular conditions.

Positive Allosteric Modulator (PAM): Enhances the effect of the natural ligand; example: benzodiazepines (e.g., alprazolam) enhance GABA effect.
Negative Allosteric Modulator (NAM): Inhibits receptor function; example: efavirenz inhibits HIV-1 reverse transcriptase.

Definition: Linking drug dose to effect. Drugs produce effects based on dose/concentration.
Importance:
- Predict drug effects at different doses.
- Compare drugs for strengths and safety.
- Basis for understanding agonists, antagonists, and modulators.

Graded Dose–Response Curve
- Measures continuous responses in an individual.
- Key Metrics: $E{max}$ (maximum effect), $EC{50}$ (dose producing 50% of $E_{max}$).
- Graphically, it is sigmoidal (log-dose vs. response).
Quantal Dose–Response Curve
- Measures all-or-none responses in a population.
- Key Metrics: $ED{50}$ (median effective dose), $LD{50}$ (median lethal dose).

Thermodynamics Equation: $ΔG = ΔH - TΔS$
- If $ΔG < 0$, the reaction is spontaneous; if $ΔG = 0$, the system is at equilibrium.
- Standard Conditions Version: $ΔG = ΔG° + RT ext{ln}Q$
- $ΔG°$ = standard Gibbs free energy change.
- $R = 8.314 ext{ J/mol·K}$ or $1.987 ext{ cal/mol·K}$.
- $T$ = temperature in Kelvin.
- $Q$ = reaction quotient.
Binding affinity is related to $ΔG°$: $ΔG° = -RT ext{ln}K<em>a$ or equivalently using $Kd$: $ΔG° = RT ext{ln}K_d$
- $Ka$ = association constant; $Kd$ = dissociation constant.

Binding ratio can be expressed as: $rac{1-y}{y}$
Equilibrium expression in receptor-ligand binding: involves free drug concentration $D$ and fraction of receptors bound $y$.

Efficacy: Greatest drug effect that can be produced ($E_{max}$).
Potency: Amount of drug needed to produce a specified effect; a drug with lower $EC{50}$ or $Kd$ is more potent.

Tolerance: Gradual decrease in drug effect; develops slowly, reversible, linked to receptor downregulation and increased metabolism (e.g., opioids).
Tachyphylaxis: Rapid decrease in effect after short-term dosing; develops quickly, caused by receptor desensitization (e.g., nasal decongestants).

Selectivity: How preferentially a drug binds to its intended receptor.
High selectivity = low affinity for other receptors = decreased off-target toxicity.

Definition: Measure of a drug's safety margin, ratio between doses causing toxic effects and those causing therapeutic effects.
- Formula: $TI = rac{TD<em>{50}}{ED</em>{50}}$
Interpretation: Higher TI indicates safer drugs; lower TI requires careful monitoring.
- Examples of wide TI: Penicillin; examples of narrow TI: Digoxin, warfarin.