Mechanism of Breathing

Key Pressures

Phase 1: Rest (Between Breaths)

• No air is moving; alveolar pressure = 0 (= atmospheric pressure), so no pressure gradient exists
• Intrapleural pressure = -5 cm H₂O; transmural pressure = +5 cm H₂O (lungs held open)
• Lung volume = FRC

Phase 2: Inspiration (Active)

• Diaphragm (main muscle) - contracts and descends, increasing thoracic volume vertically
• External intercostal muscles - contract and lift the ribs outward and upward (bucket-handle motion), increasing thoracic volume laterally and anteroposteriorly

• Scalene and sternocleidomastoid muscles - elevate upper ribs further

1. Muscle contraction → thoracic volume increases
2. By Boyle's Law (P × V = constant at constant temperature), as volume increases, pressure falls
3. Intrapleural pressure drops from -5 to about -8 cm H₂O
4. This increase in the transmural pressure gradient expands the alveoli
5. Alveolar volume increases → alveolar pressure falls to about -1 cm H₂O
6. Now alveolar pressure < atmospheric pressure; air rushes in from the atmosphere
7. Air continues to flow in until alveolar pressure returns to 0 (= atmospheric); flow ceases
8. The volume of air inhaled in one breath is the tidal volume (~0.5 L); lung volume at end of inspiration = FRC + VT

Phase 3: Expiration (Passive at Rest)

1. Inspiratory muscles relax
2. Intrapleural pressure returns toward -5 cm H₂O
3. The reduced transmural pressure no longer supports the increased lung volume
4. Elastic recoil of the stretched lung tissue compresses the alveoli
5. Alveolar pressure rises to about +1 cm H₂O (above atmospheric)
6. Air flows out of the alveoli down the pressure gradient until alveolar pressure = 0 again
7. Lung volume returns to FRC; the cycle is complete

Forced Expiration (Active)

• Internal intercostal muscles and abdominal muscles contract
• They compress the thorax, making intrapleural pressure positive
• Alveolar and airway pressures rise sharply well above atmospheric pressure
• This greatly accelerates airflow out of the lungs

Summary Table: Pressure Changes Through the Breathing Cycle

Key Concepts to Remember

• Boyle's Law governs the pressure changes: P₁V₁ = P₂V₂
• Transmural pressure (Palv - Pip) is always positive in normal breathing, keeping the lungs open
• Compliance describes how easily the lungs stretch: C = ΔV/ΔP. Low compliance (stiff lungs, e.g., pulmonary fibrosis) means more work is needed to inflate the lungs
• Airway resistance follows the Hagen-Poiseuille relationship: R = 8ηl/πr⁴. Resistance is inversely proportional to the 4th power of radius - halving airway radius increases resistance 16-fold
• FRC is the equilibrium volume where lung inward recoil = chest wall outward recoil; no muscle energy is needed to maintain it

Sources: Costanzo Physiology 7th Edition, Ch. 5 (Respiratory Physiology) | Morgan and Mikhail's Clinical Anesthesiology, 7e, Ch. 23 (Spontaneous Ventilation) | Tintinalli's Emergency Medicine, Ch. 127 (Respiratory Physiology)

Pharmacokinetics vs Pharmacodynamics

Pharmacokinetics = what the body does to the drug Pharmacodynamics = what the drug does to the body

Pharmacokinetics (PK)

• Bioavailability (F): fraction of administered dose that reaches systemic circulation
• Half-life (t½): time for plasma concentration to fall by 50%; determines dosing interval
• Clearance (CL): volume of plasma cleared of drug per unit time
• Volume of distribution (Vd): apparent volume in which a drug distributes (high Vd = extensive tissue binding)
• First-pass effect: hepatic/gut-wall metabolism before drug reaches systemic circulation (e.g. morphine oral bioavailability ~33%)

Pharmacodynamics (PD)

• Receptor interaction: most drugs bind to specific receptors (proteins, enzymes, ion channels, nucleic acids, transporters) to produce their effect. The drug-receptor complex must be sufficiently stable to modify the target system and produce an observable pharmacologic response
• Dose-response (concentration-effect) relationship: as drug concentration increases, effect increases - up to a maximal effect (Emax), at which point further increases in concentration produce no additional effect (receptor saturation)

• Agonist: binds and activates the receptor (mimics endogenous ligand)
• Antagonist: binds but does not activate; blocks the receptor (competitive or non-competitive)
• Partial agonist: activates but produces less than maximal response even at full receptor occupancy
• Inverse agonist: binds and produces the opposite effect to the agonist

Side-by-Side Comparison

Why Both Matter Together

"The overall response to a drug is determined by the interplay of multiple genes involved in both the pharmacokinetic and pharmacodynamic pathways."

• PK: oral bioavailability ~33% (heavy first-pass metabolism), t½ ~2-3 hours, mainly renal excretion of metabolites - dose must be adjusted in renal failure
• PD: binds mu-opioid receptors → inhibits adenylyl cyclase → decreased neuronal excitability → analgesia, euphoria, respiratory depression; tolerance develops with chronic use (receptor down-regulation)

Sources: Tietz Textbook of Laboratory Medicine 7th Ed., Ch. 42 | Henry's Clinical Diagnosis and Management, Ch. 75 | Katzung's Basic and Clinical Pharmacology 16th Ed., Ch. 3