Drug Injection, Metabolism & Distribution

• When a drug is injected directly into the bloodstream, 100% of it is available for distribution to tissues.

First-Pass Metabolism

• Oral drug administration requires absorption via the portal circulation.
• The "first-pass" effect involves the drug passing through the liver before reaching systemic circulation.
• During first-pass metabolism, the drug concentration is reduced due to metabolism in the liver.
• First-pass metabolism reduces the drug amount available for distribution in the tissues to less than 100%.
• Bioavailability is the percentage of administered drug that reaches the systemic circulation.

Drug Distribution

• Once in the bloodstream, a drug exists as a free drug (dissolved in plasma water) or bound to red blood cells and/or plasma proteins.
• Most drugs (95-98%) are bound in circulation, but the free drug is responsible for traversing cell membranes and producing effects.
• Protein-bound drugs act as a reservoir that slowly releases the drug, prolonging its action.
• Unbound drugs follow the concentration gradient to enter peripheral tissues.
• Tissues may contain the target site (receptor) for drug action, or be unaffected by the drug.
• Non-specific binding sites can also act as drug reservoirs.
• The volume of distribution determines the equilibrium concentration of a drug after a specific dose.
• Tissue-bound drugs eventually re-enter circulation.
• Drugs distribute into interstitial and intracellular fluids after entering systemic circulation.
• Distribution of a drug between tissues depends on vascular permeability, regional blood flow, cardiac output, tissue perfusion rate, drug binding to tissues/plasma proteins, lipid solubility, and pH partition.
• Acidic drugs accumulate in basic fluids, and basic drugs accumulate in acidic fluids due to electric charge.
• Highly-perfused organs (liver, heart, kidney) receive drugs easily, unlike less perfused tissues (muscle, fat).
• Drugs can move between plasma and tissue until equilibrium is established for the unbound amount.

Volume of Distribution

• Volume of distribution (VD) describes the relationship between drug concentration and amount in the body.
• VD shows the distribution of a drug between plasma and the rest of the body after oral or parenteral administration.
• A higher VD means greater drug distribution into tissues.
• Factors affecting VD include physical volume, drug removal/excretion rate, and drug binding with plasma proteins/tissues.

Biotransformation/Metabolism

• Biotransformation is the chemical alteration of chemicals like nutrients, amino acids, toxins, and drugs in the body.
• The body increases water solubility to excrete foreign compounds through urine.
• Drugs can undergo biotransformation:
  • Active drug to inactive metabolite
  • Active drug to active metabolite
  • Inactive drug to active metabolite
  • Active drug to toxic metabolite
• Occasionally, a parent drug is administered in an inactive form (pro-drug), and only the metabolite has activity.
• Drug biotransformation occurs in the liver which contributes to pre-systemic and systemic elimination, intestinal mucosa cells which contribute to pre-systemic elimination, and renal tubular cells and colon which is caused by bacteria.
• Drug biotransformation pathways are categorized into phase I and phase II reactions:
  • Phase I reactions include oxidative, reductive, and hydrolytic reactions where a polar group is introduced/unmasked, making the drug more water-soluble for excretion.
  • Phase I reactions are non-synthetic and result in less active metabolites.
  • Cytochrome P450 generates the majority of phase I metabolites.
  • Phase II reactions involve covalent attachment of small polar endogenous molecules (glucuronic acid, sulfate, glycine) to form water-soluble compounds, known as conjugation reactions.
  • Transferases catalyze the reaction.
  • The final compounds have a larger molecular weight.

Drug Excretion

• The liver metabolizes most drugs into inactive or less active compounds for excretion.
• Metabolites and some parent compounds may be excreted in the bile and pass out in the faeces.
• Alternatively, some drugs are reabsorbed through the GI tract.
• Parent drug and metabolites in the bloodstream are filtered by the kidney, with a portion undergoing reabsorption, and the remainder excreted in the urine.
• Some drugs are actively secreted into the renal tubule.
• Lungs eliminate alcohol and anesthetic gases.
• Small amounts of drugs are eliminated in sweat, tears, and breast milk.

When a drug is injected directly into the bloodstream, 100% of it is available. Oral drug administration requires absorption. First-pass metabolism reduces the drug amount available for distribution. Most drugs are bound in circulation.