Pharmacology Drug Absorption and Metabolism Quiz

General Pharmacology

• Pharmacology is the study of interactions between a living organism and exogenous chemicals that alter normal biochemical functions.
• Pharmaceuticals are substances with medicinal properties.
• A drug is a chemical substance used to treat, diagnose, or prevent (prophylaxis) a disease.
• Pharmacology is a chemical science practiced by pharmacologists.
• Sub-divisions include clinical pharmacology, neuro- and psychopharmacology, pharmacogenetics, pharmacogenomics, and pharmacoepidemiology. (These study drug effects on humans; behavior and nervous system function; genetic testing for drug use; application of genome technologies to drug discovery; and effects of drugs in large populations, respectively)
• Toxicology is the study of harmful effects of drugs and the practice of diagnosing and treating exposures to toxins and toxicants.
• Other subdivisions include pharmacodynamics and pharmacokinetics.

Introduction

• Pharmacodynamics is the study of what a drug does to the body and its mechanism of action.
• Pharmacokinetics is the study of what the body does to a drug — including absorption, distribution, metabolism, and excretion (ADME). (This describes how the drug moves throughout the body at the molecular level).

Routes of Drug Administration

• Drug administration routes depend on the desired therapeutic outcome and the drug's properties (e.g., water or lipid solubility, ionization).
• Enteral Routes
  • Oral: Most common route, with drugs absorbed from the gastrointestinal tract. Encounter the liver, undergo first-pass metabolism before general circulation (limits efficacy, e.g., >90% of nitroglycerin cleared by the liver). Food can affect absorption for certain drugs (e.g., insulin, penicillin).
  • Sublingual: Placement under the tongue for direct diffusion into the bloodstream and to avoid liver and potentially first-pass metabolism.
  • Rectal: 50% of rectal region drainage bypasses portal circulation, minimizing liver transformation. Aids in drug absorption for drugs affected by intestinal enzymes or low PH of stomach.
• Parenteral Routes
  • Intravascular (IV): High drug concentration in blood, rapid onset, and avoids first-pass metabolism (but risks contamination, pain).
  • Intramuscular (IM): Rapid absorption of drugs in aqueous solution. Slow absorption from depot preparations.
  • Subcutaneous (SC): Minimizes risks of intravascular injection, but some combined with epinephrine for local vasoconstriction to reduce drug removal.
  • Intradermal (ID): Injection into the dermis, usually for small volumes, like BCG vaccinations.
  • Intraarticular: Injection into the joints, e.g. for pain relief.
  • Intracardiac: Injection directly into the cardiac muscle, e.g. for cardiac arrest.
• Other Routes
  • Inhalation: For gases like anesthetics, and bronchodilators, absorption is rapid.
  • Intranasal: For drugs like desmopressin (used to treat diabetes insipidus).
  • Intrathecal/Intraventricular: For drugs needing direct entry into cerebrospinal fluid (CSF), especially in cases like acute lymphocytic leukemia.
  • Topical: Drugs applied to the skin, like creams to treat skin infections, or eyedrops.
  • Transdermal: For achieving systemic effects, usually using a patch, delivering drugs to the skin.

Absorption of Drugs

• Absorption is the transfer of a drug from its administration site to the bloodstream.
• It depends on drug transport from the GI tract, involving active and passive diffusion.
  • Passive diffusion: Drug movement from a high concentration to a low concentration region without energy; driven by the concentration gradient.
  • Active transport: Drug movement against the concentration gradient supported by energy from adenosine triphosphate (ATP) and specialized carrier proteins.
• Effect of pH: Acidic drugs absorb better in acidic conditions; basic drugs absorb better in basic conditions (pH and ionization constant pKa determine the relative concentrations of a drug's charged and uncharged forms).
• Other Factors: Blood flow influencing absorption; total absorbing areas (e.g., intestines), and how long drug remains in contact with the site

Bioavailability

• Bioavailability: The fraction of administered drug gaining access to the systemic circulation in a chemically unchanged form.
• Factors influencing bioavailability:
  • First pass hepatic metabolism
  • Drug solubility and stability
  • Drug formulation: affects rate of absorption
• Bioequivalence: Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.

Drug Distribution

• Distribution: The process by which a drug moves from the bloodstream to the interstitial fluid of tissues and eventually into specific cellular compartments.
• Blood flow plays a key role
• Capillary permeability: Hydrophobic drugs cross capillaries more easily; ionized forms are absorbed less readily or not at all.
• Binding of drugs to plasma proteins (e.g., albumin): This binding creates a reservoir of drug; only unbound drug can act on its target site.
• Blood-brain barrier: Lipid-soluble drugs cross the blood-brain barrier more readily than water-soluble drugs.

Volume of Distribution (Vd)

• Volume of Distribution (Vd): A hypothetical volume of fluid into which the drug is disseminated.
• Factors affecting Vd include blood flow, capillary permeability, and drug binding to proteins.
• The compartments of body water are used to compare Vd.
• Vd = Dose given/plasma concentration

Drug Metabolism (Biotransformation)

• Metabolism refers to reactions that convert a drug into a metabolite with changed properties, enabling possible excretion or further metabolism. This typically occurs in the liver, but other tissues can be involved.
• Kinetics of metabolism:
  • First order kinetics: Drug metabolism rate is proportional to drug concentration.
  • Zero order kinetics: Drug metabolism rate is constant, regardless of drug concentration. This occurs at high doses when the enzymes involved are saturated or the metabolizing agents are rate-limiting.
• Reactions of metabolism:
  • Phase I reactions: Oxidation, reduction, hydrolysis, resulting in more polar molecules which can then undergo more excretion.
  • Phase II reactions: Conjugation reactions making drugs more water-soluble and enabling excretion.
  • Factors influencing drug metabolism, such as CYP450, in different phases

Drug Elimination

• Elimination: Removal of drugs and their metabolites from the body.
• Elimination methods:
  • Renal elimination: Glomerular filtration; tubular secretion; active secretion
  • Hepatic elimination: Metabolism by the liver, excretion into the bile
    -Other routes: Include lung, milk, and enterohepatic circulation for some drugs.
• Body clearance: Total body clearance (CLTotal) is the sum of the clearances from all the eliminating organs (e.g., kidney, liver).
• First order elimination kinetics: Drug concentration decreases exponentially during the course of elimination
• Clinical situations resulting in increased drug half-life, thus requiring dosage adjustments: factors include reduced kidney function, drug-drug interactions.