Pharmacokinetics and Drug Action

Study Notes

The body's action on the drug, including absorption, distribution, metabolism, and elimination.
Medicinal chemists must understand these properties to design effective drugs.

The drug's action on the body, including physiological response, mechanism of action, and dose-response curve.

Slight modifications in a drug's structure can cause dramatic activity changes, often related to specific physical factors.

Partition coefficient (log P): Relates to the drug's solubility in lipids versus water.
Dissociation constant (pKa): Determines the ionization state of a drug at different pHs, impacting absorption and distribution.
Steric factor: Relates to the size and shape of the molecule, impacting binding, absorption, and metabolism.
Solubility: The ability of a drug to dissolve in a solvent, directly impacting absorption.
Polymorphism: Different crystal forms of a drug, potentially affecting solubility and dissolution rate.

Parenteral: Injections, including IV, IA, intraspinal, IM, SC, and IP. This bypasses the gastrointestinal tract, offering faster absorption.
Gastrointestinal Tract (GIT): Oral administration, requiring drug dissolution in GIT fluids. The dissolution rate depends on:
- Particle size: Smaller particles have greater surface area, promoting faster dissolution.
- pH of the medium: Weakly acidic drugs dissolve better in basic regions of the GIT and vice versa.

Active transport: Energy-requiring transport against the concentration gradient. Requires similarity between the drug and the natural substrate.
Passive diffusion: Drug movement down the concentration gradient, no energy required.
Convective absorption: Passive transport of small molecules through water-filled pores in the membrane.

Rate of diffusion is proportional to the drug concentration at the absorption site.
Important factors influencing passive diffusion:
- Area of the membrane: Larger area, faster diffusion.
- Thickness of the membrane: Thinner membrane, faster diffusion.
- Partition coefficient of the drug: Higher lipid solubility, faster diffusion through cell membranes.

Most drugs are either weak acids or weak bases.
Henderson-Hasselbalch Equation:
- For weak acids: pH = pKa + log ([salt]/[acid])
- For weak bases: pH = pKw - pKb + log ([base]/[salt])

The ratio of a drug's concentration in an organic phase to its concentration in an aqueous phase at equilibrium.
Higher log P values indicate greater lipid solubility.

Protein binding: Drugs can bind to proteins in the bloodstream.
- Advantages: Act as a temporary storage site, releasing free drug slowly, potentially contributing to longer duration of action.
Metabolism: The process of breaking down drugs in the body.
Excretion: Eliminating the drug from the body.
Storage sites: Drugs accumulate in specific tissues, such as neutral fat.

Drugs can partition into neutral fat based on factors like:
- Partition coefficient: Log P
- Ionization constant: pKa

For a drug to be excreted in urine:
- Polarity: Drugs need to be polar to be eliminated in urine.
- pH manipulation: Adjusting urine pH can enhance excretion.