Pharmacokinetics and Pharmacodynamics Lecture Review
Pharmacokinetics (movement of drugs through the body)
Kinetics comes from kinesis = motion; pharmacokinetics = how drugs move through the body and what happens to them on that journey.
Four basic principles of pharmacokinetics:
Absorption
Distribution
Metabolism
Excretion
These four processes describe the journey from administration to exit; the lectures return to this framework between sections.
Absorption
Definition: movement of a drug from the site of administration into the bloodstream.
Key questions: how fast effects begin (rate of absorption) and how strong the effects are (extent of absorption).
Why absorption matters: determines site-of-action drug concentration, helps estimate maximum effect, and informs safety/efficacy.
Drug entry into cells and crossing the cell membrane:
Cell membrane barrier is a phospholipid bilayer; many drugs cross by direct penetration if lipophilic.
Three main routes across the membrane:
Direct penetration of the membrane (primary route for many drugs).
Transport systems (may require energy, e.g., ATP; can be selective).
Channels/pores (used by very small ions; most drugs are too large).
Lipid solubility and the principle of ālike dissolves likeā: lipophilic (lipid-soluble) drugs cross membranes more easily; water-soluble drugs cross less easily.
Ionization and pH effects:
Drugs are acids or bases. Acids are proton donors; bases are proton acceptors.
Ionization affects absorption location and efficiency because ionized forms cross membranes poorly.
Example: aspirin (acetylsalicylic acid) is an acid; in the stomach (acidic pH) it remains largely non-ionized and is absorbed; in the small intestine (more basic environment) aspirin ionizes and absorption decreases.
HendersonāHasselbalch intuition (brief): for acids, pH = pKa + log([A^-]/[HA]); for bases, pH = pKa + log([B]/[BH^+]). Ionization state shifts with pH and affects absorption.
Absorption factors that enhance absorption (rate and extent):
Rate of dissolution
Surface area at the absorption site
Blood flow to the site
Lipid solubility
pH partitioning (the ionization state in local pH)
Absorption factors: practice question note
Drug absorption is enhanced by dissolution rate, surface area, blood flow, and lipid solubility, and by favorable pH partitioning; absorption is not enhanced when ionization favors ionized forms (ionized forms absorb poorly).
Routes of administration (two broad categories):
Enteral (GI tract): oral, NG tubes, G-tubes, etc.
Parenteral (outside GI tract): injections (IV, IM, subcutaneous, etc.).
Intravenous (IV) administration:
Fastest route; absorption is essentially instantaneous and complete (no barriers to absorption).
Advantages:
Rapid onset
Precise control of the drug amount entering the systemic circulation
Can dilute irritating drugs by giving with fluids
Disadvantages/risks:
High cost of fluids and equipment; requires specialized training
Irreversible once administered (cannot āpull backā into syringe)
Risk of fluid overload, infection, embolism
Concentration and dosage may differ from oral forms (e.g., morphine IV vs oral)
Intramuscular (IM) and Subcutaneous (SC) administration:
Absorption depends on blood flow and tissue access; it can be rapid or slow
Advantages:
Good for drugs that do not cross membranes easily
Depot preparations allow slow, extended absorption (months/weeks)
Disadvantages:
Less convenient; discomfort; potential tissue injury or nerve damage
Oral (per os) administration:
Absorption occurs in the GI tract after dissolution and barrier crossing into the bloodstream
Advantages:
Easy, convenient, lower cost, reversible
Disadvantages:
High variability in absorption between individuals
May be inactivated by stomach acid or digestive enzymes; gastric pH variations affect absorption
Local GI irritation possible; may require enteric coatings to control dissolution and rate
Factors affecting oral absorption (recap):
Drug dissolution rate and formulation (e.g., coatings)
Gastric emptying time and intestinal transit
Presence of food or other drugs (food effects)
Practical teaching point:
As a nurse, you cannot arbitrarily change the route of administration; route selection is a decision in the clinical plan and scope of practice.
Distribution
Definition: movement of a drug from the blood to tissues and cells to reach the site of action.
Determinants: three main factors govern distribution:
Blood flow to tissues
Ability of the drug to exit capillary beds (capillary permeability)
Ability of the drug to enter cells
Special distribution considerations:
Bloodābrain barrier (BBB): tight junctions protect CNS; crossing is harder; some drugs cross via cellular penetration or active transport; those crossing well often have specific properties.
Placenta: provides a barrier to drugs; P-glycoprotein transporters pump some drugs back to maternal blood; some drugs still cross to fetus, explaining fetal exposure and, in some cases, drug-related neonatal effects.
Albumin binding: many drugs bind to plasma albumin; if bound, they stay in the bloodstream and do not readily exit to tissues. Binding can be reversible; displacement or changes in albumin levels alter free drug concentration and effect.
Implications: distribution can affect drug levels at the site of action, potential toxicity, and interactions through displacement from albumin or competition for transporters.
Metabolism (Biotransformation)
Definition: body alters the drugās chemical structure to modify activity and toxicity; most metabolism occurs in the liver.
Key enzyme system: hepatic cytochrome P450 family (CYP450) drives many metabolic reactions and drug interactions (the lecture references the liverās enzyme system, commonly known as the CYP450 system).
Six possible metabolic outcomes (and their significance):
Accelerated excretion by increasing water solubility (most important clinical effect)
Inactivation of the drug (active drug becomes inactive)
Increased therapeutic action (drug is activated or made more potent)
Prodrugs (inactive or less active compound that is activated by metabolism)
Increased toxicity (bioactivation to toxic metabolites)
Decreased toxicity (reduced harmful effects)
First-pass effect (pre-systemic metabolism): orally administered drugs may be extensively metabolized in the liver before reaching systemic circulation, potentially abolishing activity; if this occurs, alternative routes (e.g., IV) may be used to bypass first-pass metabolism.
Additional factors affecting metabolism:
Age: infants have immature liver function; metabolism rates increase as liver matures (by about 1 year); elderly may have reduced metabolic capacity.
Drugādrug interactions: some drugs induce (activate) or inhibit liver enzymes, altering the metabolism rate of themselves or co-administered drugs.
Excretion
Definition: how drugs exit the body; primary route is via the kidneys, but other routes exist (breath, sweat, skin, and excretion via GI tract).
Renal excretion processes:
Glomerular filtration: drugs pass from blood through Bowman's capsule into urine (drugs must be small enough; mostly unbound in plasma).
Tubular reabsorption: some drugs are reabsorbed back into the bloodstream from the tubular filtrate.
Active tubular secretion (P-glycoprotein and other transporters): transporters pump drugs back into the urine for elimination.
Other excretion routes:
Breath (exhalation), sweat, and skin (sweat and dermal excretion)
Clinical relevance: accumulation and clearance rates affect drug levels; monitoring drug concentrations helps maintain efficacy while avoiding toxicity.
Drug concentrations and safety concepts
Drug concentration correlates with effect: higher drug levels generally produce greater effects up to a point.
Key concentration concepts:
Minimum effective concentration (MEC): the lowest concentration to achieve a therapeutic effect.
Therapeutic range: concentration range where the drug is effective with minimal harm; between MEC and toxic concentration.
Toxic concentration: concentration at which harm surpasses benefit.
Pharmacokinetic definitions:
Half-life (
t_{1/2}
): time required for drug concentration to decrease by half.Plateau / steady state: when drug intake sustains a level where fluctuations average out around a consistent concentration; achieved after repeated dosing aligned with half-life.
Loading dose: an initial larger dose to rapidly achieve the therapeutic concentration when a long time to reach plateau would otherwise delay effect.
Pharmacodynamics (drug effects on the body)
Definition: the study of how drugs exert biochemical and physiological effects; the relationship between dose and response.
Core concepts:
Doseāresponse relationship: as dose increases, response typically increases (graded response).
Maximal efficacy: the largest effect a drug can produce; not always the best choice (safety and necessity matter).
Potency: the amount of drug needed to produce a given effect; less drug required = higher potency (not necessarily better).
Receptors: drugs act via receptors (hormones, neurotransmitters, etc.) which must bind to produce effects; binding is reversible generally.
Receptor interactions and effects:
Receptors are like locks; drugs are keys; binding can turn on (agonist) or block (antagonist) receptor function.
Agonist: activates receptor to mimic normal body action (e.g., opioids). Antagonist: blocks receptor to prevent action (e.g., antihistamines, Narcan). Antagonists can prevent allergy symptoms by blocking histamine receptors.
Selectivity: the degree to which a drug acts on a given receptor relative to others; higher selectivity means fewer off-target effects.
Receptor theories:
Simple occupancy theory: response proportional to number of occupied receptors; does not explain potency differences well.
Modified occupancy theory: incorporates affinity (how strongly a drug binds) and intrinsic activity (ability to activate receptor) to explain varying potencies and efficacies.
Affinity: the strength of attraction between drug and receptor; higher affinity means a drug can achieve effect at lower concentrations (often linked to higher potency).
Intrinsic activity: the ability of a drug to activate a receptor once bound; higher intrinsic activity yields a stronger response (think of a light switch dimmer vs full on).
Receptors and dose concepts:
ED50 (average effective dose): the dose required to produce a therapeutic effect in 50% of the population; a starting point for dosing:
ED_{50}
LD50 (average lethal dose): the dose that is lethal in 50% of animals tested; used to calculate safety margins.
Therapeutic Index (TI): safety measure, defined as the ratio of LD50 to ED50:
A wider TI indicates a safer drug; a narrow TI requires careful dosing and monitoring.
Practical receptor concepts:
Multiple drugs can occupy receptors; selectivity reduces off-target effects but does not guarantee safety.
Agonists vs antagonists illustrated:
Agonist example: morphine activating opioid receptors to reduce pain.
Antagonist example: Narcan (naloxone) binding and blocking opioid receptors to reverse overdose.
Antihistamines act as antagonists at histamine receptors to prevent allergic symptoms when exposed to allergens.
Integration and clinical implications
Pharmacokinetics informs pharmacodynamics (what the body does to the drug vs what the drug does to the body).
Dosing decisions depend on: route of administration, absorption variability, distribution to target tissues, metabolism and excretion rates, and patient-specific factors (age, organ function, interactions).
First-pass effect can render an oral dose ineffective, driving route decisions (e.g., IV bypassing hepatic first-pass).
Drug interactions may alter metabolism (enzyme induction/inhibition) and distribution (e.g., competition for albumin binding).
Monitoring drug concentrations and patient response helps tailor therapy to maintain the therapeutic range and avoid toxicity
. Additionally, understanding the half-life of drugs is crucial for determining dosing intervals and achieving desired blood levels without causing adverse effects.
Half-life and plateau (conceptual):
t_{1/2} = \text{time required for concentration to decrease by 50%}
Plateau/steady state is reached when intake and elimination balance over dosing intervals.
First-pass effect (concept): orally administered drugs may be extensively metabolized in the liver before entering systemic circulation, potentially eliminating activity and necessitating alternative routes.
Depot/arc dosing (concept): depot injections provide slow, extended release to maintain therapeutic levels without frequent dosing.
End of pharmacokinetics and pharmacodynamics notes
Review focus areas for exams:
Remember the four pharmacokinetic processes and how they influence dosing decisions.
Understand absorption determinants and why routes differ in onset and intensity.
Recognize distribution factors (BBB, placenta, albumin binding).
Grasp metabolism and the role of CYP450; first-pass effects and age-related changes.
Know excretion pathways and renal handling (filtration, reabsorption, active secretion).
Distinguish pharmacodynamics concepts: doseāresponse, potency, efficacy, receptors, occupancy theory, and agonist/antagonist effects.
Use TI, ED50, and LD50 to think about safety margins and dosing strategies.