Pharmacokinetics 3 and Drug Distribution

Core Focus: Understanding the movement of drugs within the body (ADME: Absorption, Distribution, Metabolism, and Excretion).

Fundamental Concepts

Rate and Extent:
- Rate: The speed at which a drug moves from the systemic circulation (blood) into various interstitial and intracellular fluids.
- Extent: The degree to which a drug disperses into the tissues. This is essentially the movement of the parent drug from the blood to tissues after administration, followed by its return from tissues to blood during the elimination phase.
Volume of Distribution (Vd): A theoretical volume used to quantify the distribution of a drug. It is calculated as: Vd = Total amount of drug in the body/Drug concentration in plasma
- A high Vd indicates the drug is sequestered in tissue (like fat), while a low Vd suggests the drug remains primarily in the circulatory system.

Interactions Affecting Distribution

Plasma Protein Binding: Only the free (unbound) drug is pharmacologically active and capable of crossing membranes.
- Albumin: The primary protein for binding acidic drugs (e.g., Warfarin, Naproxen).
- $\alpha_{1}$ -acid glycoprotein: The primary protein for binding basic drugs (e.g., Propranolol, Lidocaine).
Tissue Binding: High affinity for specific tissue components (e.g., tetracycline binding to calcium in bones/teeth) can increase the $V_d$ .

Homeostatic Function: Protects the CNS by maintaining a highly regulated chemical environment. It effectively limits the entry of potentially toxic substances and many therapeutic drugs.
Physiological Basis:
1. Tight Junctions: Continuous intercellular occlusions between endothelial cells of the brain capillaries prevent paracellular transport.
2. Glial End-Feet: Astrocytes surround the capillaries, adding another layer of physical and metabolic resistance.
3. Efflux Transporters: Active transport systems like P-glycoprotein (P-gp) (an ABC transporter) actively pump drugs back into the blood.
Area Postrema: Known as the 'Chemoreceptor Trigger Zone' (CTZ), this region lacks a tight BBB, allowing it to detect toxins in the blood and trigger the emetic center (vomiting reflex).

Permeabilities and Solubility

Lipid Solubility: This is often measured by the partition coefficient ( $P$ ). Lipid-soluble molecules pass through the endothelial cell membranes via passive diffusion.
- High Solubility: Thiopentone (rapid onset for anesthesia).
- Moderate/Low Solubility: Phenobarbital cross significantly slower.
- Water-Soluble/Polar: Salicylate or highly ionized molecules enter the brain minimally unless there is an active transport mechanism.

Example: Therapeutic Strategies in Parkinson's Disease

Dopamine Paradox: Parkinson’s involves a deficiency of dopamine in the substantia nigra. However, dopamine itself cannot cross the BBB because it is a polar molecule at physiological $pH$ .
Levodopa ( $L-DOPA$ ): The precursor to dopamine. Unlike dopamine, it is transported across the BBB via the Large Neutral Amino Acid Transporter (LAT1).
Clinical Application: $L-DOPA$ is converted to dopamine in the brain by the enzyme DOPA decarboxylase. It is often administered with a peripheral decarboxylase inhibitor (like Carbidopa) to prevent premature conversion in the blood.

Equilibrium Concept: The state where the free drug concentration in the tissue equals the free drug concentration in the plasma.
Two-Compartment Model Phases:
- Phase 1 (Distribution Phase): Rapid decline in plasma concentration as the drug moves from the central compartment (blood/well-perfused organs) to peripheral tissues.
- Phase 2 (Elimination Phase): A slower decline representing the removal of the drug from the body via metabolism or excretion.

Perfusion Rate ( $ml/min/g$ of tissue): Determines the delivery of the drug to specific organs. Highly perfused organs reach equilibrium significantly faster.
1. Lungs: $10$ (Highest perfusion; receives the entire cardiac output).
2. Kidneys: $4.5$
3. Vessel Rich Group: Heart ( $0.6$ ), Brain ( $0.55$ ), Liver ( $0.8$ ).
4. Adipose Tissue (Fat): $0.03$
5. Muscle (Resting): $0.025$
6. Bone: $0.02$

Case Study: Thiopentone Redistribution

Mechanism: Thiopentone is highly lipid-soluble and quickly enters the brain (high perfusion). However, its effect is short ( $15-30$ minutes) not because of metabolism, but due to redistribution. The drug leaves the brain and moves into less perfused but high-capacity tissues like skeletal muscle and eventually fat.

The Necessity of Metabolism

Polarization: The primary goal of metabolism is to make lipid-soluble drugs more water-soluble (polar), allowing them to be excreted by the kidneys (as the renal tubule would otherwise reabsorb lipid-soluble drugs).

Phases of Metabolism

Phase 1 (Functionalization):
- Introduces or unmasks a functional group (e.g., $-OH$ , $-NH_{2}$ , $-SH$ ).
- Major reactions: Oxidation (primarily via Cytochrome P450 enzymes), Reduction, and Hydrolysis.
- Example: Conversion of Benzene to Phenol.
Phase 2 (Conjugation):
- Attachment of a large, polar endogenous molecule to the functional group created in Phase 1.
- Processes: Glucuronidation, Sulfation, and Acetylation.
- Result: The metabolite is usually larger, highly ionized, and inactive.
- Example: Phenol converted to Phenyl Sulfate ( $99.99\%$ ionized, high water solubility).

Clinical Variability

Enzyme Saturation: At therapeutic doses, most metabolic enzymes work at first-order kinetics (not saturated).
Biological Factors: Metabolism varies based on:
- Genetics: Polymorphisms in CYP enzymes (e.g., fast vs. slow acetylators).
- Age: Reduced enzyme activity in neonates and the elderly.
- Disease: Liver cirrhosis or heart failure (reduced perfusion to the liver) can significantly impair drug clearance.