Pharma - Berto - L5 part 1

Routes of Administration

• Administration routes are divided into enteral (oral, sublingual, rectal) and parenteral (intravenous, intramuscular, cutaneous, subcutaneous, inhalatory, transcutaneous, transmucosal).
• Oral administration is most common but suffers from first-pass metabolism reducing bioavailability.
• Sublingual and rectal routes can bypass first-pass metabolism, providing advantages.
• Intravenous routes quickly achieve maximum drug concentration but require careful administration to avoid damage.
• Intramuscular route, cutaneous route (for diagnostics), and subcutaneous route (for insulin delivery) are also important parenteral methods.
• Inhalation can elicit systemic or local effects, influenced by particle size and delivery.

Absorption and Effects

• Different administration routes lead to varying peak concentrations and therapeutic effects.
• Intravenous administration results in rapid peak concentration followed by quick decline, increasing risk of toxicity.
• Oral and intramuscular routes produce lower peak concentrations, allowing for prolonged therapeutic effects.
• Elimination kinetics are similar across routes; differences lie in initial peak and duration of drug effect.

Distribution Factors

• Distribution occurs among three fluid compartments: plasma, extracellular, intracellular.
• Influential factors in drug distribution include blood flow, partition coefficient, and protein binding.
• Plasma proteins, primarily albumin (acidic drugs) and alpha-1-acid glycoprotein (basic drugs), are crucial for drug binding.
• Factors such as age and diseases can modify plasma protein concentrations, influencing drug actions.

Volume of Distribution

• Apparent volume of distribution (Vd) indicates how a drug is distributed across body compartments, not reflecting real anatomical volumes.
• High Kp (tissue concentration/plasma concentration) suggests greater drug presence in tissues; low Kp indicates the opposite.

Drug Metabolism

• Drug metabolism detoxifies substances, primarily occurring in the liver through two phases: functionalization (Phase I) and conjugation (Phase II).
• Phase I reactions can activate or inactivate drugs through oxidation, reduction, and hydrolysis.
• Cytochrome P450 enzymes play a vital role in drug oxidation; CYP3A4 is notable for metabolizing various substances.
• Phase II includes conjugation reactions, which usually convert drugs to more hydrophilic forms for easier elimination.

Toxic Metabolites

• Metabolism can yield toxic metabolites; paracetamol is an example that can cause hepatotoxicity due to a reactive metabolite when overdosed, requiring antidote acetylcysteine.

Cytochrome P450 System

• Cytochrome P450 complex is essential for drug metabolism, comprising multiple isoenzymes with a significant presence in the liver.
• Important isoforms for drug metabolism include CYP3A4, CYP2D6, and CYP2C9.
• Cytochrome P450 catalyzes reactions in a series of steps involving substrate interaction and electron transfer from NADPH.

Hydrolysis and Other Reactions

• Hydrolysis reactions, catalyzed by enzymes like esterases, unmask functional groups for Phase II processing.
• Non-cytochrome dependent oxidative reactions involve soluble enzymes in the cytoplasm for metabolism of certain substances, such as alcohol.

Summary

• Understanding the pharmacokinetics of drug administration (routes, absorption, distribution, metabolism) is crucial for effective therapeutic interventions and minimizing adverse effects.