Pharmacology Chapter on Drug Absorption

Pharmacokinetics

• Pharmacokinetics is the study of how drugs move throughout the body.
• It's necessary to achieve drug action.
• Four processes involved are absorption, distribution, metabolism (biotransformation), and excretion (elimination).

Drug Absorption

• The movement of the drug into the bloodstream after administration.
• Different routes affect absorption rates:
  • Enteral (by mouth): Drugs absorbed across the lining of the small intestine.
  • Intramuscular: Drugs absorbed faster in muscles with higher blood flow.
  • Subcutaneous: Slower absorption due to decreased blood flow compared to muscle.
  • Rectal: Slower absorption due to smaller surface area and lack of villi.

Drug Absorption - For Drugs Taken By Mouth (Enteral)

• Most oral drugs are absorbed across the mucosal lining of the small intestine.
• The lining is covered with villi to increase surface area for absorption.
• Reduced villi can decrease absorption due to disease, drug effects, or removal of the small intestine.
• After absorption, drugs enter the liver via the portal vein.
• In the liver, some drugs are metabolized to an inactive form, which is excreted, reducing the active drug amount. This is first-pass metabolism.

Drug Absorption - Mechanisms of Absorption (Enteral)

• Passive Transport: Drugs move across the membrane without energy, from high to low concentrations (Diffusion & Facilitated Diffusion).
• Active Transport: Drugs move against their concentration gradient, requiring a carrier (enzyme or protein).
• Pinocytosis: Cells engulf drug particles in a vesicle.

Drug Absorption - Dissolution

• For the body to use drugs taken by mouth (solid form), they must dissolve into small particles in a liquid to form a solution.
• This process is called dissolution.
• Tablets aren't 100% drug; fillers (excipients) like syrup, gums, and honey improve dissolution.

Drug Absorption - Disintegration

• Disintegration is the breakdown of a drug into smaller particles.
• Drug disintegration and dissolution occur faster in acidic fluids (pH 1-2) compared to alkaline fluids (pH > 7).
• Enteric-coated drugs resist disintegration in the stomach acid, dissolving only in the alkaline environment of the small intestine.

Bioavailability

• The percentage of administered drug available for activity.
• Affected by absorption and first-pass metabolism.
  • Orally administered drugs usually have less than 100% bioavailability.
• Factors affecting bioavailability:
  • Drug form, administration route, gastric mucosa and motility, administration with food/other drugs, and liver function.

Factors Affecting Drug Absorption

• Blood flow
• Pain
• Fasting
• Food
• pH
• Stress
• Hunger
• Exercise

Intramuscular Absorption

• Drugs injected into muscles are absorbed faster where blood flow is higher.

Subcutaneous Absorption

• Absorption is slower in subcutaneous tissue than in muscle due to lower blood flow.

Rectal Absorption

• Slower absorption than oral route due to smaller surface area and a lack of villi in the rectum.

Drug Distribution

• Drug movement from circulation to body tissues.
• Influenced by:
  • Rate of flow to tissue
  • Drug affinity to tissue
  • Protein binding

Protein Binding

• As drugs are distributed in the plasma, many bind to plasma proteins (albumin, lipoproteins, alpha-1-acid-glycoprotein [AGP]).
• Acidic drugs (aspirin, methotrexate) & neutral drugs (nortriptyline) bind with albumin or lipoproteins. Basic drugs (morphine, amantadine) bind to AGP.
• Highly protein-bound drugs are >90% bound to protein (Warfarin, Glyburide, Sertraline, Furosemide, Diazepam).
• Bound portion is inactive; unbound portion is free and active.
• Low plasma protein levels can increase free drug, leading to accumulation and toxicity.

Blood-Brain Barrier (BBB)

• The BBB protects the brain from foreign substances (about 98% of drugs); tight junctions in the brain capillaries prevent most substances from crossing.
• Lipid-soluble drugs (e.g., benzodiazepines) may cross through diffusion.
• Water-soluble drugs struggle to cross.

Drug Metabolism (Biotransformation)

• The body chemically changes drugs into a form that can be excreted.
• Liver is the primary site of metabolism.
• Liver enzymes (cytochrome P450 system) convert lipid-soluble drugs into water-soluble metabolites.
• Water-soluble metabolites are then excreted.

Drug Half-Life

• The time it takes for the amount of a drug in the body to reduce by half.
• Factors affecting half-life include the amount of drug administered, previous doses, metabolism, and elimination.
• Half-life is used to determine the dosing interval.

Steady State

• A stable drug concentration in the body.
• Achieved when the rate of drug administration equals the rate of drug elimination.

Drug Excretion

• Elimination of drugs from the body. - Kidneys are the primary route of excretion. - Other routes include bile, lungs, saliva, sweat, and breast milk. - Kidneys filter free drugs, water-soluble drugs; drugs bound to protein aren't filtered.

Factors Affecting Drug Excretion

• Urine pH: Acidic urine promotes excretion of weak base drugs; alkaline urine promotes excretion of weak acid drugs.
• Prerenal conditions: reduced blood flow to kidneys decreases glomerular filtration.
• Intrarenal conditions: affect glomerular filtration and tubular secretion/reabsorption.
• Post renal conditions: adversely affect glomerular filtration.

Common Tests to Determine Renal Function

• Creatinine: Metabolic by-product of muscle, excreted by the kidneys.
• Blood Urea Nitrogen (BUN): Breakdown product of protein metabolism.

Pharmacodynamics

• The study of how drugs affect the body.
• A drug's primary effect is its desired response.
• Secondary effects may be desirable or undesirable.

Dose-Response Relationship

• The body's physiological response to changes in drug concentration at the site of action.
• Potency- Amount of drug needed to achieve a specific response. (low potency-needs more drug for the desired response)
• Maximal efficacy- Point where increasing the dose no longer increases the desired effect.
• Therapeutic Index (TI)- The difference between the therapeutic dose (ED50) and the toxic dose (TD50); high TI is safer.
• ED50 (effective dose in 50% of the population)
• TD50 (toxic dose in 50% of the population)

Onset, Peak, and Duration of Action

• Onset: Time it takes for a drug to reach the minimum effective concentration (MEC).
• Peak: Highest drug concentration in the blood.
• Duration: Length of time a drug exerts its therapeutic effect.

Therapeutic Drug Monitoring (TDM)

• Plasma drug level: Highest concentration of the drug at a specific time, used to measure and monitor absorption rates.
  • Peak time (oral 2-3 hrs; IV 30-60 mins; IM 2-4 hrs)
• Trough drug level: Lowest drug concentration, measures drug elimination. Drawn right before the next dose.

Receptor Theory

• Most receptors are proteins on cell surface membranes or within the cell.
• Four receptor families:
  • Cell membrane-embedded enzymes
  • Ligand-gated ion channels
  • G protein-coupled receptor systems
  • Transcription factors

Agonists and Antagonists

• Agonists: Drugs that activate receptors and produce a desired response.
• Antagonists: Drugs that prevent receptor activation, blocking a response.

Nonspecific and Nonselective Drug Effects

• Nonspecific: Drugs affecting multiple receptor sites, potentially producing undesirable effects besides the target site.
• Nonselective: Drugs affecting multiple receptors, leading to multiple bodily effects (desirable/undesirable).

Mechanisms of Drug Action

• Stimulation: Drugs enhancing intrinsic activity (e.g., increasing heart rate).
• Depression: Drugs decreasing neural/bodily function (e.g., decreasing heart rate).
• Irritation: Drugs causing a noxious effect.
• Replacement: Drugs replacing essential body compounds (e.g., insulin).
• Cytotoxic action: Drugs selectively killing invading organisms/cancers.
• Antimicrobial medication: Drugs preventing, inhibiting, or killing infectious organisms.
• Modification of immune system: Drugs modifying/enhancing/depressing the immune system.

Side Effects, Adverse Drug Reactions, and Drug Toxicity

• Secondary effects of drug therapy (desirable/undesirable).
• Adverse drug reactions can be unexpected, unintentional, while taking normal dosage, due to chronic illness, age, weight, gender, and ethnicity..
• Drug toxicity occurs when drug levels exceed the therapeutic range, potentially from overdose, accumulation, disease, genetics, or age.

Pharmacogenetics

• Study of how genetics affect an individual's response to a specific drug.
• Genetic factors can change drug metabolism.
• Can impact the absorption, distribution, metabolism, and excretion of the drug.
• Pharmacogenomics aims to develop precision medicine based on a person's genetic makeup to enhance outcomes and safety.

Drug Interactions

• An altered or modified drug action or effect due to one or more drugs.
  • Pharmacokinetic interactions: Changes in absorption, distribution, metabolism, or excretion of one or more drugs.
  • Pharmacodynamic interactions: Additive, synergistic, or antagonistic drug effects (combining two drugs with additive effects means that the combined effect of the two drugs is potentially greater than the sum of the individual effects. Synergistic effect- two drugs combining to produce a response greater than the effects of each drug. Antagonistic effect -two drugs that combine, and one drug reduces or blocks the effect of the other drug).
• Common symptoms of drug-drug interactions: nausea, heartburn, headache, and lightheadedness.
• Drug-nutrient interactions: Food can affect the body's response to drugs.
• Drug-laboratory interactions: Drugs can affect clinical lab tests.

Drug-Induced Photosensitivity

• Skin reaction caused by a drug and exposure to UV light.
• Photoallergic reaction: Drug activates in the skin with UV light into a more allergenic compound & requires previous exposure.
• Phototoxic reaction: Drug undergoes photochemical reaction with UV light to cause damage & doesn't involve the immune system, dose-related.

Examples of Drugs that Cause Photosensitivity

• (List of Drugs)