Pharmacokinetics | Drug Absorption

Pharmacokinetics Overview

Introduction to Pharmacokinetics

• The video introduces pharmacokinetics, emphasizing its importance for understanding drug absorption and administration.

• Viewers are encouraged to follow along with diagrams and comprehensive notes available on the website.

Routes of Drug Administration

• Absorption is defined as the process by which a drug enters circulation after administration.

• Common routes of administration include:

• Oral (PO)

• Rectal (suppository)

• Intravenous (IV)

• Inhaled

• Buccal (between lip and teeth)

• Sublingual (under the tongue)

Mechanisms of Absorption

• The most common route is oral, where drugs must pass through the gastrointestinal tract to enter the bloodstream.

• Key mechanisms for drug absorption depend on drug characteristics, including size and hydrophobicity.

Passive Diffusion

• Simple or passive diffusion allows small, hydrophobic drugs to cross cell membranes from high to low concentration areas.

• Characteristics necessary for passive diffusion include being small and hydrophobic, enabling easy passage through lipid bilayers.

Active Transport Mechanisms

Drug Transport Mechanisms

Facilitated Diffusion

• Drugs can move from areas of high concentration to low concentration through facilitated diffusion, which requires specific proteins for transport across cell membranes.

• The characteristics of the drug, such as size and solubility (hydrophobic vs. hydrophilic), determine its ability to utilize facilitated diffusion.

Active Transport

• Active transport moves drugs from low concentration to high concentration, requiring energy in the form of ATP; this process is not passive.

• Large hydrophilic drugs are transported via active transport mechanisms that pump them against their concentration gradient.

Routes of Drug Administration

• Different routes (oral, rectal, intradermal, subcutaneous, intramuscular) require drugs to pass through various cell layers before entering the bloodstream.

• Intravenous administration is unique as it allows direct entry into the bloodstream without crossing a membrane.

Bulk Transport and Endocytosis

• For very large molecules (e.g., Vitamin B12), bulk transport may be necessary when no transporter exists for their size.

• This process involves binding to receptors on cell membranes and triggering endocytosis, allowing large drugs to enter cells and subsequently exocytose into circulation.

Summary of Absorption Mechanisms

• Four primary mechanisms facilitate drug absorption:

• Passive diffusion (small hydrophobic molecules)

• Facilitated diffusion (large hydrophilic molecules with protein carriers)

• Active transport (large hydrophilic molecules using ATP)

• Endocytosis (for excessively large molecules).

Factors Affecting Drug Absorption

Influences on Absorption Efficiency

• Various factors can affect drug absorption including pH changes, blood flow variations, surface area differences, and gastrointestinal transit speed.

Importance of pH in Drug Formulation

• The pH level influences whether a drug exists in an ionized or non-ionized form; weak acids dissociate into protons and conjugate bases affecting absorption rates.

Charged Molecules and Membrane Permeability

Understanding Drug Absorption in Different pH Environments

The Role of pH in Drug Absorption

• Weak acids and their absorption: A weak acid drug is more easily absorbed in a nonpolar, uncharged form. This occurs when the environment has fewer protons, making it less negatively charged.

• Importance of proton concentration: To enhance drug absorption, the reaction must favor the formation of the nonpolar form by increasing proton concentration in the environment.

• Application of Le Chatelier's Principle: Increasing protons shifts the equilibrium towards forming more weak acid (HA), which is better absorbed across cell membranes.

• Acidic environments for absorption: Weak acids are best absorbed in acidic environments like the proximal duodenum, where they exist predominantly as HA.

• Stomach vs. proximal duodenum: While drugs can be introduced into an acidic environment via the stomach, significant absorption occurs primarily in the proximal duodenum due to its acidity.

Transitioning Between Forms

• Conversion between forms: Weak acids can exist as either polar (charged) or nonpolar (uncharged). The goal is to convert them to their nonpolar form for optimal absorption.

• Mechanism for conversion: To shift from polar to nonpolar, one must increase proton levels, creating a highly acidic environment conducive to absorption.

Understanding Weak Bases

• Characteristics of weak bases: Unlike weak acids, weak bases such as amphetamines are better absorbed in alkaline conditions found further down the gastrointestinal tract (distal ileum).

• Reaction dynamics for weak bases: A typical weak base dissociates into a polar part (BH⁺), which is not easily absorbed, and a nonpolar part (B), which is readily absorbed.

• Shifting reactions for absorption: To favor absorption of weak bases, one needs to decrease proton concentration by creating an alkaline environment that shifts equilibrium towards B.

Optimal Sites for Absorption

• Best sites for drug absorption based on pH:

• Weak Acids: Best absorbed in proximal duodenum due to acidic conditions.

• Weak Bases: Best absorbed in distal ileum where conditions are more alkaline.

Blood Flow and Drug Absorption

Understanding Drug Absorption and Its Influencing Factors

Impact of Blood Flow on Drug Absorption

• The absorption of drugs into the bloodstream is significantly affected by blood flow to organs. Reduced blood flow can lead to decreased absorption, particularly in shock states such as septic, cardiogenic, or hypovolemic shock.

• In shock states, decreased blood flow results in diminished absorption from the gastrointestinal (GI) tract and skin, leading to less drug entering the bloodstream.

• Oral or rectal medications will have reduced absorption during shock due to poor perfusion; intravenous administration is preferred for guaranteed drug delivery.

Role of Contact Time and Surface Area

• Conditions like diarrhea can accelerate GI transit time, reducing contact time for drug absorption and thus decreasing overall effectiveness.

• Conversely, constipation increases contact time within the GI tract, allowing more opportunity for drugs to be absorbed effectively.

• Weak acids are best absorbed in acidic environments (proximal duodenum), while weak bases thrive in alkaline conditions (distal ileum).

Effects of Diseases on Absorption

• Diseases that damage intestinal structures (e.g., microvilli and villi), such as inflammatory bowel disease or celiac disease, decrease total surface area available for absorption.

• A reduction in surface area directly correlates with decreased drug absorption capabilities; conditions causing diarrhea further exacerbate this issue.

Multi-drug Resistance Mechanisms

• Some patients may develop multi-drug resistance due to p-glycoprotein transporters that expel drugs back into the GI tract instead of allowing them into circulation.

• This mechanism inhibits effective drug absorption and is commonly observed in various resistant bacterial infections or treatment scenarios.

Summary of Key Factors Affecting Drug Absorption

Understanding Bioavailability in Drug Administration

What is Bioavailability?

• Bioavailability refers to the fraction of a drug that enters systemic circulation, crucial for understanding how much of the administered dose is available for therapeutic effect.

Routes of Drug Administration

• The two primary routes discussed are intravenous (IV) and oral (PO). IV administration bypasses all membranes, delivering 100% of the drug directly into the bloodstream.

• In contrast, oral administration often results in less than 100% bioavailability due to various factors affecting absorption.

Factors Affecting Oral Bioavailability

• Several factors influence how much of an orally administered drug reaches systemic circulation:

• pH levels

• Blood flow patterns

• Surface area contact time

• Drug solubility (lipophilic vs. hydrophilic)

• Not all orally taken drugs will reach their full potential concentration in the bloodstream; this can vary significantly based on individual characteristics and drug properties.

Comparing IV and Oral Administration

• When comparing concentrations over time, IV drugs maintain a higher concentration initially, while oral drugs may peak lower due to absorption issues.

• The area under the curve (AUC) is used to quantify bioavailability differences between IV and oral routes.

Calculating Bioavailability

• The formula for calculating bioavailability is:

[

textBioavailability = fractextAUC_textoraltextAUC_textIV

]

• For example, if you administer 100 mg IV and only absorb 50 mg orally, then the bioavailability would be calculated as:

• If AUC(oral)=50 mg and AUC(IV)=100 mg → Bioavailability = 50/100 = 0.5 , or 50%.

Importance of Understanding Bioavailability

• Recognizing these concepts is vital for determining appropriate dosing strategies depending on whether a drug is given intravenously or orally.

Understanding Drug Bioavailability

Factors Affecting Bioavailability

• Lipophilic (nonpolar) drugs have higher bioavailability as they easily pass through cell membranes, leading to greater absorption into the bloodstream.

• Conversely, hydrophilic (water-loving) and larger molecules exhibit decreased absorption, resulting in lower bioavailability.

• Solubility is a critical factor; lipid-soluble drugs are absorbed more effectively than hydrophilic ones due to their ability to cross cell membranes.

Instability and Administration Routes

• The stability of a drug in its administration environment significantly impacts its bioavailability. For instance, penicillin G is poorly absorbed orally due to degradation by stomach acid.

• High levels of hydrochloric acid can destroy penicillin G before it reaches systemic circulation, necessitating alternative routes like IV or IM administration.

• Enzymatic breakdown also affects bioavailability; for example, proteases in the GI tract can degrade insulin when taken orally, rendering it ineffective.

First-Pass Effect

• The first-pass effect refers to the metabolism of a drug after it enters the portal system but before reaching systemic circulation. This process occurs primarily in the liver.

• After oral administration, drugs travel from the GI tract through the hepatic portal system to the liver where they may be metabolized and lose potency.

• A significant portion of administered drugs may be lost during this process; for example, if 100 mg is given but only 90 mg reaches the portal system, further loss occurs in the liver.

Impact on Systemic Circulation

• If 60 mg out of 90 mg is metabolized by the liver, only 30 mg will enter systemic circulation. This illustrates how drastically bioavailability can decrease from oral administration compared to IV routes.

• Understanding these dynamics is crucial for determining appropriate dosing strategies and ensuring effective therapeutic outcomes based on drug formulation and route of administration.

Understanding Drug Administration and Bioavailability

The Importance of Delivery Routes

• Nitroglycerin is commonly administered sublingually to avoid first-pass metabolism, which significantly reduces the amount of drug that reaches systemic circulation.

• Various administration routes (IV, topical, intramuscular, etc.) bypass the liver's first-pass effect, allowing more drug to enter the bloodstream compared to oral administration.

• For example, if 100 mg of nitroglycerin is taken orally, only about 10 mg may reach systemic circulation due to extensive first-pass metabolism in the liver.

• To maximize bioavailability and therapeutic effects, alternative routes like sublingual or IV are preferred for drugs susceptible to significant first-pass metabolism.

Understanding Bioavailability

• Bioavailability refers to the proportion of a drug that enters systemic circulation when introduced into the body. IV administration achieves 100% bioavailability.

• Factors affecting bioavailability include solubility; small lipophilic drugs generally have higher absorption rates than large hydrophilic drugs.

• Drugs degraded by gastric pH or proteases will have reduced bioavailability; thus, understanding these factors is crucial for effective drug delivery.

Clinical Application: Drug Overdose Scenario

• In cases of drug overdose, intravenous (IV) administration is ideal as it ensures 100% bioavailability of antidotes compared to other routes like oral or subcutaneous.

Absorption Characteristics of Weak Basic Drugs

Optimal Conditions for Absorption

• A weak basic drug with a pKa close to physiological pH will be better absorbed in an alkaline environment such as the distal ileum rather than in acidic conditions.

• The dissociation equilibrium described by Le Chatelier’s principle indicates that reducing proton concentration (making it more alkaline) favors absorption of nonpolar forms of weak bases.

Conclusion on Drug Absorption Sites

Understanding Drug Absorption and pH Levels

The Role of pH in Drug Absorption

• The jejunum is identified as the most basic environment for drug absorption, which is crucial for weak bases. This area has a pH that is approximately 0.2 units away from the drug's pKa, optimizing absorption.

• A close relationship between the pH and the pKa of a weak base enhances its solubility and absorption in the gastrointestinal tract.

Transition to Distribution Phase

• The discussion transitions from pharmacokinetics related to absorption to distribution, indicating a shift in focus within the pharmacokinetic series.