Pharmacodynamics and Receptors

Pharmacodynamics

• It refers to the actions or effects of a drug on the body.
• It determines the drug's classification and its suitability as a therapy for a specific disease or symptom.

Receptor

• The part of a cell or organism that interacts with a drug.
• This interaction starts a series of events leading to the drug's effects.
• Receptors are specific molecules in a biological system that drugs interact with to change the system's function.
• Receptors determine the qualitative relationships between the dose or concentration of a drug and its effects.
• Most receptors are proteins.
• The receptor site, also a recognition site, is where the drug binds.
• The interaction between drug and receptor starts the drug's action.

Receptor Classifications

• Regulatory Proteins: the most characterized drug receptors that mediate the effects of the most useful therapeutic agents
• Enzymes: inhibited (or less commonly, activated) by binding a drug
• Transport Proteins: facilitate the movement of molecules across biological membranes
• Structural Proteins: provide support and stability to cells and tissues

Effector

• Molecules that translate drug-receptor interaction into a change in cellular activity
• Some receptors can also be effectors

Transmembrane Signaling Mechanisms

• Intracellular receptors: Ligands bind to these to regulate gene transcription in the nucleus.
• Ligand-regulated enzymes: Ligand binding induces receptor dimerization
• Cytokine receptors: Transmembrane receptor that binds and stimulates a protein tyrosine kinase.
• Ligand-gated ion channels: Regulate the opening of ion channels.
• G protein-coupled receptors: Transmembrane receptor is coupled with an effector which modulates production of an intracellular second messenger.

Intracellular Messengers

• Cyclic adenosine monophosphate
• Calcium and phosphoinositides
• Cyclic guanosine monophosphate

cAMP

• Mediates hormonal responses.
• Stimulates the mobilization of stored energy (breakdown of carbohydrates in the liver).
• Stimulation of membrane enzyme phospholipase C is the crucial step in calcium and phosphoinositides.
• Beta-adrenergic catecholamines stimulates heart rate and contraction
• Catecholamines mediate hormonal responses
• Vasopressin mediates conservation of water by the kidneys
• Parathyroid hormone is responsible for calcium homeostasis
• Calcium and Phosphoinositides bind to receptors linked to G proteins while others bind to receptor tyrosine kinases.
• cGMP has signaling roles in intestinal mucosa and vascular smooth muscle cells.
• In cGMP, relaxation of vascular smooth muscles is caused by Kinase-Mediated Mechanism.

Graded dose-response curve

• A response of a receptor-effector system measured against increasing drug concentrations.
• It graphs the response versus the drug dose
• The smaller the EC50, the greater the potency of the drug.
• Efficacy (Emax) and Potency (EC50) are derived from this curve.
• Emax is the maximal response a drug can produce, signifying all receptors are occupied.
• No response, even if the dose is increased
• EC50 is the concentration of drug that produces 50% of maximal effect.
• Bmax is the total number of receptor sites, it means that all receptors have been occupied.
• Kd is the equilibrium dissociation constant, measuring the concentration of drug required to bind 50% of the receptors
• Smaller Kd means greater affinity of the drug to the receptor.
• Agonist response occurs in the absence of antagonist on curve A
• On curve B, the maximal response is preserved because the remaining available receptors are still in excess.
• Curve C appears after a larger concentration of antagonist, where receptors are not spare, but sufficient to mediate an undiminished maximal response.
• Curves D and E: With higher antagonist concentrations, the number of available receptors reduces to the point where the maximal response diminishes.
• Coupling is the transduction process between receptor occupancy and specific effect production.

Spare receptors

• Maximal drug response achieved at less than maximal receptor occupation.
• Inert Binding Sites are non-regulatory molecules.
• Binding results in no detectable change in the biologic system's function.
• Agonist binds to the receptor directly/indirectly, bringing about an effect
• Partial Agonist produces less than the full effect, even when it has saturated the receptors.
• Antagonist acts as an inhibitor in the presence of a full agonist and binds but does not activate the receptors.
• Antagonists block or compete with agonists.

Antagonist Classifications

• Competitive Antagonist: Binds reversibly without activating the effector system.
• Clinical response depends on the concentration of agonist that is competing for the binding receptor to reach the same maximal effect
• Irreversible Antagonist: Binds with the receptor via covalent bonds and may have high affinity.
• Unless spare receptors are present, there is no increase in median effective dose (ED50).
• This does not depend on interaction with the agonist's receptor.
• Chemical Antagonism: Drug interacts directly with the antagonized drug to remove it/prevent it from reaching its target.
• Physiological Antagonism: Utilizes of the regulatory pathway, it binds to a different receptor, producing an effect opposite to the drug it is antagonizing.
• Receptor Desensitization: Response diminishes even if the drug is still present.
• Structure Activity Relationship: Cells use more than one signaling mechanism to respond to the drug.
• Quantal Dose-Response Curve:
• ED50 (Median Effective Dose): 50% of individuals manifest the desired therapeutic effect.
• TD50 (Median Toxic Dose): 50% of individuals manifest toxic effects.
• LD50 (Lethal Dose): Dose causing death in 50% of the tested population.
• Therapeutic Index: Ratio of the TD50 or LD50 to the ED50.
• Therapeutic Window: Dosage range between the minimum effective therapeutic concentration/dose and the minimum toxic concentration/dose
• False; large toxic dose. A very safe drug might be expected to have a smaller toxic dose.

Maximal Efficacy

• Maximal effect that an agonist can produce if taken to very high levels.
• Determined mainly by the nature of receptors and associated effectors.
• It is only measured with the graded dose-response curve.
• Potency is the amount of drug needed to produce a given effect.
• The effect chosen in the quantal graded dose-response curve

Variables in quantal dose-response curve

• ED50: 50% of the individuals manifested the desired therapeutic effect
• TD50: 50% of the individuals manifested the toxic effects.
• LD50: the dose of a drug or toxic substance that causes death in 50% of a tested population (usually in animal studies).
• Idiosyncratic Response: An unknown or unusual response.
• Caused by differences in metabolism (genetic) or immunologic mechanisms.
• Hyporeactive Response: Intensity of the drug is decreased, or reduced to no response, and needs a large dose of the drug to have an effect.
• Hypereactive Response: Intensity of the drug is increased or exaggerated.
• Tolerance: Decreased sensitivity acquired due to exposure and develops after a few doses.
• Tachyphylaxis: Tolerance is acquired because of exposure.
• Down Regulation: Decrease in the number of receptors.
• Up Regulation: Increase in the number of receptors.
• Overshoot Phenomenon/Rebound Hypertension: When a drug taken for a long time is abruptly discontinued.
• Reduce this by gradually decreasing/tapering the dose.
• Clinical Sensitivity: Gives the drug that really acts on the disease.
• Drugs are selective by the receptor but never specific
• Beneficial and toxic effects may be mediated by the same receptor-effector mechanism

Ways to avoid/circumvent effects of a drug

• Give low doses.
• Carefully monitor the patient.
• Employ ancillary procedures.
• Use a safer drug.
• Heparin:
• Low doses: prevention of blood clots.
• Very high doses: causes internal bleeding.
• Monitor PT, PTT, and bleeding parameters.
• Steroids:
• Give lowest dose possible.
• Give adjunctive drugs.
• Anatomic selectivity (lungs-by inhalation).

Pharmacodynamics is the study of a drug's effects on the body, influencing its therapeutic use. Receptors, often proteins, are key to this process. They interact with drugs to initiate a series of events that alter the system's function.