Principles of Clinical Neuropharmacology

Mechanism

Mechanism · Pharmacodynamic hysteresis

In the CNS, the clinical response usually shows temporal hysteresis with respect to the plasma concentration. For example, antidepressants immediately inhibit monoamine reuptake, but clinical therapeutic effect requires 2 to 4 weeks. This delay responds to the need for downregulation of presynaptic autoreceptors (5-HT_1A and α₂) and the consequent gene transcription cascade mediated by CREB and the induction of BDNF (Brain Derived Neurotrophic Factor).

Pharmacokinetics

1. Physiology of the Blood-Brain Barrier (BBB) and Transport Kinetics

The BBB limits the diffusion of xenobiotics through a system of tight junctions (tight junctions) composed of occludins, claudins and endothelial adhesion molecules, supported by the podocytes of astrocytes. The penetration of a drug depends on its lipid solubility (octanol/water partition coefficient, P), degree of ionization at physiological pH (7.4) and affinity for active efflux transporters.

Transcellular Passive Diffusion Equation (Fick's Law) J = - D \cdot P \cdot \frac{\Delta C}{\Delta x} Where J is the net flux, D the diffusion coefficient, P the partition coefficient and \Delta C/\Delta x the concentration gradient.

P-glycoprotein (P-gp), encoded by the ABCB1 gene, is an ATP-binding cassette (ABC) transporter that exerts unidirectional active efflux back into the systemic circulation. P-gp inducing or inhibitory drugs drastically alter the brain concentrations of psychotropics without substantially modifying their plasma levels.

2. Receptor Dynamics and Binding Kinetics

The affinity of a psychotropic drug for its target is defined by the equilibrium dissociation constant (K_d or K_i), measured in nanomolar (nM).

Receptor Occupancy Ratio (Hill-Langmuir Equation) \text{Ocupación} = \frac{[F]}{[F] + K_d} The higher the affinity, the lower the K_d value and the lower the necessary drug concentration [F] to saturate 50% of the targets.