Pharmacology: Dynamics and Kinetics

• General pharmacology
  • Concerns the effects of drugs on the human body
  • Also addresses the body's response to drugs

Pharmacodynamics

• Investigates how drugs affect physiological events and explores their mechanisms
• Focuses on what drugs do to the body

Pharmacokinetics

• Examines the absorption, how the body processes, distributes, and eliminates drugs along with drug measurements
• Focuses on what the body does to drugs

Absorption

• The process where drugs move from application areas into the bloodstream

Distribution

• How a drug reaches the place where it is intended to have an effect

Metabolism

• How the body processes the drug

Excretion

• The removal of the drug from the body

Pharmacokinetic Properties

• Determine the concentration of a drug at its site of effect

Bioavailability

• Measures how much the body benefits from a drug administered for systemic effect
• Oral bioavailability references the amount of orally administered drug that reaches the inferior vena cava and then arterial blood circulation

Drug Absorption Defined

• The passage of a drug from the administration site into the bloodstream or lymphatic circulation
• Local effects desired, absorption is not preferred
• Systemic effects, the faster a drug is absorbed, the quicker its action begins
• Bioavailability is the extent to which a drug is absorbed from its site of administration

Mechanisms of drug passage through cell membranes

• Passive diffusion
• Facilitated diffusion
• Active transport
• Endocytosis / exocytosis

Passive Diffusion

• Drugs move from areas of high concentration to areas of low concentration
• Diffusion occurs passively through aqueous channels in intercellular junctions or directly across lipid cell membranes
• Requires no energy or carrier
• Is the most significant mechanism for drug passage across membranes

Facilitated Diffusion

• Transition from high to low concentration, similar to passive diffusion
• A carrier is required
• It is a saturable process
• Requires no energy

Active Transport

• Drugs move against the concentration gradient, from low to high concentration areas
• Carrier required
• Energy is necessary, usually in the form of ATP
• It is a saturable process

Endocytosis / Exocytosis

• Process that involves moving large molecules or particles into or out of the cell
• Drugs like peptide hormones, growth factors, and antibodies bind to receptors on the cell surface
• Ligand-receptor complexes form and are internalized into endosomes
• Require cellular energy (ATP)

Factors Affecting Rate of Drug Absorption

• Drug-related
• Physicochemical properties of the drug molecule
• Pharmaceutical formulation of the drug
• Drug concentration
• Pharmacological properties of the drug

Physicochemical Properties

• The smaller the molecular size and the greater the lipid solubility (lipophilicity) of the drug results in faster absorption

Pharmaceutical Form

• For solid dosage forms like tablets or coated pills, disintegration and dissolution must occur before absorption
• The rate of these processes influences the overall absorption rate
• Suspensions and emulsions are absorbed more slowly than solutions
• Absorption speed comparison: Solution > Emulsion > Suspension > Capsule > Tablet > Coated Tablet

pH and Drug Absorption

• Drug absorption depends on the pH levels of the stomach and intestines
• Weak acids (e.g., aspirin) are better absorbed in low pH environments (stomach) because they remain in a non-ionized form
• This allows them to cross cell membranes more easily
• Weak bases (e.g., codeine) are better absorbed in high pH environments (intestines)
• This is because they exist in a non-ionized form, promoting passage through cell membranes

Drug Concentration

• Higher drug concentration at the administration site leads to faster absorption

Pharmacological Properties

• Vasoconstrictor drugs reduce blood flow, slowing absorption
• Vasodilator drugs increase blood flow, enhancing absorption

Route of Administration

• Orally administered drugs take time to reach the small intestine, where absorption begins
• Injection routes (intramuscular, subcutaneous) lead to faster absorption
• Drugs administered intravenously are considered absorbed immediately

Surface Area for Absorption

• The larger the surface area, the greater and faster the drug uptake
• Drugs administered via inhalation are absorbed across the large surface area of the alveoli
• Inhaling a general anesthetic leads to quick anesthesia

Gastric Emptying

• Drugs taken on an empty stomach with plenty of water pass quickly into the duodenum and are absorbed faster
• Taking a drug on an empty stomach refers to the period starting 2 hours after the last meal and ending 1 hour before the next one

Intestinal Motility

• In conditions like diarrhea or constipation, the rate of absorption may decrease

Drug Distribution

• Drug molecules enter the bloodstream and distribute into three major physiological fluid compartments after absorption

Plasma

• Makes up approximately half of total blood volume

Interstitial Fluid Compartment

• Includes water that fills body cavities and spaces between cells, as well as cerebrospinal fluid (CSF)
• Capillaries transport drugs to the interstitial fluid after absorption

Intracellular Fluid Compartment

• Refers to fluids within the cells
• Some drugs can enter inside the cells
• Plasma drug molecules bind to plasma proteins at varying rates

Protein-Bound Drugs

• Pharmacologically inactive
• Act as a reservoir
• When free drug molecules are eliminated from circulation, the bound drug is gradually released, prolonging the action duration
• Some drugs can strongly bind to tissues and become stored
• Tissue storage of drugs can lead to prolonged therapeutic and extended side effects

Redistribution of Drugs

• Highly lipid-soluble drugs, administered rapidly via intravenous or inhalation routes, initially accumulate in highly perfused organs (brain, heart, kidneys)
• After a short time, the drug redistributes into adipose (fat) tissue
• This alters the original distribution pattern
• Inhaled general anesthetics and thiopental concentrate heavily in the brain during the first few minutes, then up to 70% redistributes to adipose tissue within hours, reducing the effect as the drug leaves the target site

Drug Metabolism (Biotransformation)

• After administration, drugs are exposed to the action of enzymes
• Biotransformation is the chemical modification of drugs through enzymatic activity
• Result: drugs usually become less active or completely inactive

Prodrugs

• Inactive compounds that are converted into an active form in the body
• The metabolic process can change the drug's effect and pharmacokinetic properties
• Results in changes in polarity, increased water solubility and easier excretion

Drug Metabolites

• The compounds formed as a result of drug metabolism

Drug Metabolism Location

• Enzymes responsible for drug metabolism are more concentrated in certain organs
• The liver contains the richest quantity and variety of enzymes
• Drugs can also be metabolized in the gastrointestinal mucosa, lungs, and kidneys
• Other organs involved include the skin, central nervous system (CNS), plasma, and red blood cells (erythrocytes)

Drug Metabolism Phases

• Drug metabolism typically occurs in two phases

Phase I

• Involves chemical reactions like oxidation, reduction, and hydrolysis

Phase II

• The drug or its metabolites are conjugated (joined) with certain compounds in a process called conjugation
• Some drugs are eliminated only after undergoing Phase I reactions

Drug Excretion (Elimination)

• Drugs or their metabolites are primarily eliminated via the kidneys
• Some are excreted through the liver via bile
• Gases and volatile liquids are eliminated through the lungs
• Excretion can occur in saliva and breast milk

Drug Half-life (t½)

• The time required for the drug's plasma concentration to be reduced by half through elimination pathways

Receptors

• A receptor is a site on or within a cell which:
  • Selectively binds with high affinity to endogenous active substances (autacoids or neurotransmitters)
  • Binding also occurs to drug molecules with similar structures

Receptor Functions

• Recognition of drugs and other molecules (endogenous or exogenous)
• Transmission of the chemical signal into the cell by acting as a biological signal
• Converting a chemical signal into a biological response through signal transduction

Agonist

• A drug that binds to a receptor and fully activates it, producing a maximal response
• Example: Salbutamol (Albuterol), a β₂-adrenergic agonist that binds to β₂ receptors in smooth muscle, causing bronchodilation, and is used in asthma attacks to rapidly open airways

Antagonist

• A drug that binds to a receptor but does not activate it
• Instead, it blocks the action of an agonist
• Example: Propranolol, a β-blocker (β₁ and β₂ antagonist) that blocks β₁ receptors in the heart, reducing heart rate and blood pressure, used in hypertension and arrhythmias, and counteracts the effects of natural catecholamines like adrenaline

Partial Agonist

• A drug that binds to a receptor and produces a weaker response than a full agonist
• Partial agonist is administered with a full agonist, it can reduce or block the full agonist’s effects
• Buprenorphine, a partial μ-opioid receptor that agonist provides limited analgesia compared to morphine
• It competes with full agonists, making it useful in opioid dependence treatment for adhesion