---

Pharmacokinetics & Pharmacodynamics

PART 1: GENERAL PHARMACOKINETICS (PK)

---

A. Routes of Drug Administration

---

B. Absorption

1. Lipid solubility: Lipid-soluble, non-ionized drugs cross membranes more readily.
2. Ionization (Henderson-Hasselbalch): Only the unionized fraction can cross membranes. Weak acids are better absorbed in the acidic gastric environment; weak bases in the alkaline intestine.
3. Molecular size: Smaller molecules cross membranes more readily.
4. First-pass effect: Oral drugs absorbed from the GI tract pass through the portal circulation and liver before entering systemic circulation, where significant metabolism may reduce bioavailability.
5. P-glycoprotein efflux pump: Located at intestinal epithelium - pumps drugs out of enterocytes, reducing absorption and contributing to multidrug resistance.

• IV administration = 100% bioavailability.
• Calculated as: F = AUC(oral) / AUC(IV) × 100%

---

C. Distribution

1. Plasma protein binding: Drugs bound to albumin (acidic drugs) or alpha-1-acid glycoprotein (basic drugs) are pharmacologically inactive and cannot be distributed to tissues. Only free (unbound) drug is active.
2. Volume of Distribution (Vd):
   • Vd = Amount of drug in body / Plasma drug concentration
   • Small Vd: drug stays in blood (high protein binding, hydrophilic)
   • Large Vd: drug distributes extensively to tissues (lipophilic)
3. Tissue compartments: Highly perfused organs (brain, heart, liver, kidneys) equilibrate rapidly (vessel-rich group). Muscle, fat, and bone equilibrate more slowly.
4. Blood-brain barrier (BBB): Only lipid-soluble, non-ionized, low-molecular-weight drugs penetrate readily.
5. Redistribution: After initial distribution to highly perfused tissues, drug redistributes to less-perfused tissues (e.g., thiopental - rapid CNS effect then redistribution to muscle/fat causes rapid awakening).

---

D. Metabolism (Biotransformation)

Phase I Reactions (Functionalization)

• Introduce or expose a polar functional group (-OH, -NH₂, -SH) via oxidation, reduction, or hydrolysis.
• Cytochrome P450 (CYP) system: Primary Phase I system. Located in hepatic endoplasmic reticulum.
  • Key isoforms: CYP3A4/5 (most abundant; metabolizes ~50% of drugs), CYP2D6, CYP2C9, CYP2C19, CYP1A2
  • CYP3A4 also found in intestinal mucosa - contributes to first-pass metabolism of drugs like cyclosporine, midazolam
  • Genetic polymorphism: CYP2D6 - "poor metabolizers" lack the enzyme (codeine gives no benefit as it can't be activated to morphine); "ultrarapid metabolizers" convert codeine too fast, risking opioid toxicity in breastfed infants
• May increase, decrease, or have no effect on pharmacologic activity.
• Prodrugs are activated by Phase I (e.g., codeine → morphine; clopidogrel → active thienopyridine).

Phase II Reactions (Conjugation/Synthetic)

• Conjugation with glucuronide, sulfate, acetate, glutathione, or methyl groups.
• Products are generally inactive (exceptions: morphine-6-glucuronide is active) and water-soluble for renal/biliary excretion.
• Occur simultaneously with or after Phase I.

CYP Inducers & Inhibitors

• Inducers (increase CYP expression → faster drug metabolism → reduced effect): rifampin, carbamazepine, phenytoin, barbiturates, St. John's Wort
• Inhibitors (reduce CYP activity → reduced metabolism → increased drug levels/toxicity): ketoconazole, erythromycin, grapefruit juice, fluoxetine

---

E. Elimination & Pharmacokinetic Parameters

Renal Excretion

• Glomerular filtration: Free (unbound) drug filtered.
• Active tubular secretion: Organic acid/base transporters actively secrete drugs into tubular lumen.
• Passive tubular reabsorption: Lipid-soluble/unionized drugs reabsorbed back into blood. Urine pH manipulation alters reabsorption (acidifying urine traps basic drugs; alkalinizing traps acidic drugs - used in overdose management).

Half-life (t½)

• Time for plasma drug concentration to decrease by 50%.
• t½ = 0.693 × Vd / Clearance
• ~3.3 half-lives to reach 90% of steady state; ~5 half-lives to reach full steady state.
• Clinically: drugs are typically considered eliminated after 5 half-lives.

Clearance (CL)

• Volume of plasma cleared of drug per unit time (mL/min).
• CL = Dose / AUC = Vd × Ke (elimination rate constant)
• Hepatic clearance can be flow-limited (high-extraction drugs like lidocaine) or capacity-limited (low-extraction drugs like warfarin).

Steady State (C_ss)

• Achieved when rate of drug administration equals rate of elimination.
• Reached in ~4-5 half-lives regardless of dosing interval or dose size.
• Dosing frequency affects peak-trough fluctuation but NOT the C_ss level; dose size affects C_ss level.

Zero-order vs First-order Kinetics

• First-order: Rate of elimination proportional to plasma concentration (constant fraction eliminated per unit time) - applies to most drugs.
• Zero-order: Rate of elimination is constant regardless of concentration (constant amount eliminated per unit time) - occurs at saturating concentrations (e.g., alcohol, phenytoin, aspirin at high doses); these drugs have no true half-life and can accumulate unpredictably.

---

PART 2: GENERAL PHARMACODYNAMICS (PD)

---

A. Drug-Receptor Interaction

Types of Drug-Receptor Interaction

Competitive vs Non-competitive Antagonism

• Competitive (reversible): Antagonist competes with agonist for same receptor site; overcome by increasing agonist dose. Shifts dose-response curve to the right (increased EC50, same Emax).
• Non-competitive (irreversible/allosteric): Cannot be overcome by increasing agonist. Reduces Emax.

B. Dose-Response Relationships

• Potency (EC50): Concentration producing 50% of maximal effect. A drug with lower EC50 is more potent.
• Efficacy (Emax): The maximum effect a drug can produce. A drug can be highly potent but have low efficacy.
• Therapeutic index (TI): TI = TD50 / ED50 (ratio of toxic dose to effective dose). Drugs with narrow TI require careful monitoring (e.g., digoxin, lithium, aminoglycosides).

C. Signal Transduction (Receptor Types)

1. Ligand-gated ion channels (Type I): Fast onset (milliseconds). Example: nicotinic acetylcholine receptor (Na⁺/K⁺ flux), GABA-A receptor (Cl⁻ flux), NMDA receptor.
2. G-protein coupled receptors (GPCRs, Type II): Seconds to minutes. Examples:
   • Gs → adenylyl cyclase → ↑cAMP (β-adrenergic, glucagon)
   • Gi → ↓cAMP (α2-adrenergic, opioid)
   • Gq → phospholipase C → IP3/DAG (α1-adrenergic, muscarinic M1/M3)
3. Enzyme-linked receptors (Type III): Hours. Examples: insulin receptor (tyrosine kinase), cytokine receptors.
4. Intracellular/nuclear receptors (Type IV): Hours to days (gene transcription). Examples: steroid hormones (glucocorticoids, sex hormones), thyroid hormone.

D. Drug Tolerance & Tachyphylaxis

• Tolerance: Reduced drug effect with repeated dosing (may involve receptor downregulation, enzyme induction, or physiologic adaptation).
• Tachyphylaxis: Rapid tolerance occurring with very short repeated exposures (e.g., tyramine, ephedrine - due to catecholamine depletion).
• Physical dependence: Adaptive state manifest as a withdrawal syndrome upon abrupt discontinuation.

---

---

PART 3: PHARMACOKINETICS OF INHALATIONAL ANESTHETIC AGENTS

---

A. The FA/FI Concept

• FA = alveolar concentration (also called the end-tidal concentration, which reflects brain partial pressure at equilibrium)
• FI = inspired concentration being delivered
• A rapid rise in FA/FI = faster induction of anesthesia.

---

B. Factors Increasing FA/FI (Speed of Induction)

1. Inspired Concentration / Fresh Gas Flow

• Higher FI drives FA/FI up faster.
• Concentration effect: With highly concentrated agents (especially N₂O at high inspired concentrations), uptake into blood of large volumes of gas concentrates remaining gas in alveoli, causing FA to rise faster than expected.
• Second gas effect: When N₂O is co-administered with a potent volatile agent, the rapid uptake of N₂O concentrates the volatile agent in the alveolus, accelerating its rate of rise.

2. Alveolar Ventilation

• Increasing minute ventilation (respiratory rate or tidal volume) delivers more fresh anesthetic to alveoli, increasing FA/FI.
• This is especially important for agents with higher blood solubility (e.g., older agents like halothane), where increased ventilation can partially compensate for slow uptake.

3. Functional Residual Capacity (FRC)

• Large FRC = larger "reservoir" of gas that must be "washed in" with anesthetic, slowing rise in FA/FI.
• N₂O given as 75% of inspired gas must fill the FRC before FA begins to rise efficiently.

---

C. Factors Decreasing FA/FI (Blood & Tissue Uptake)

V̇B = λb/g × Q × (PA - Pv) / PB

• λb/g = blood:gas partition coefficient
• Q = cardiac output
• PA = alveolar partial pressure
• Pv = mixed venous partial pressure
• PB = barometric pressure

1. Blood:Gas Partition Coefficient (Solubility)

• A low blood:gas coefficient means the drug is poorly soluble in blood → blood quickly becomes saturated → less uptake from alveoli → FA rises quickly → faster induction.
• A high coefficient means blood acts as a large reservoir, continuously taking up drug → FA rises slowly → slow induction.
• By the same logic, emergence is faster with low-solubility agents (desflurane, sevoflurane) because elimination from blood to alveoli is rapid.

2. Cardiac Output (Q)

• High cardiac output (e.g., anxiety, hyperthyroidism): More blood circulates through the lungs per minute, picking up more anesthetic from alveoli → FA/FI rises MORE slowly (paradoxically, high CO slows induction for soluble agents).
• Low cardiac output (e.g., shock, heart failure): Less uptake → FA/FI rises faster → risk of overdose (especially important clinically in critically ill patients).
• For low-solubility agents, cardiac output has little influence because blood becomes saturated quickly regardless.

3. Alveolar-Venous Partial Pressure Difference (PA - Pv)

• At the start of induction, Pv = 0 (no anesthetic in venous blood) → maximum uptake gradient.
• As induction proceeds, tissues absorb anesthetic → Pv rises → gradient narrows → uptake slows → FA/FI rises.

---

D. Distribution (Tissue Uptake)

• Brain equilibrates rapidly with arterial blood → anesthetic effect begins quickly once arterial levels rise.
• Fat acts as a large sink for lipid-soluble agents; with prolonged anesthesia, fat continues to accumulate drug, prolonging emergence.
• The tissue:blood partition coefficient (or tissue solubility) determines how much drug each tissue can hold at equilibrium.

---

E. Elimination (Emergence)

• Inspired concentration reduced to zero → FA falls.
• The rate of fall of FA (and thus brain concentration) depends on:
  • Blood:gas partition coefficient (low solubility = fast emergence)
  • Duration of anesthesia: With prolonged procedures, fat becomes saturated; continued release from fat into blood maintains brain levels → slower emergence.
  • Alveolar ventilation: Higher ventilation speeds washout, especially for soluble agents.
  • Cardiac output: Has less influence on emergence than induction.

Diffusion Hypoxia (Fink Effect) with N₂O

• On discontinuing N₂O, large volumes of N₂O rapidly exit blood into alveoli, diluting alveolar O₂ and CO₂.
• Transient decrease in alveolar PO₂ → hypoxia.
• Prevented by giving 100% O₂ for at least 5-10 minutes at the end of N₂O anesthesia.

---

F. Metabolism

• Compound A: Produced when sevoflurane reacts with desiccated CO₂ absorbent (especially Baralyme > soda lime) - nephrotoxic in rodents, clinical significance in humans remains debated.
• Carbon monoxide: Desflurane > isoflurane > sevoflurane degrade to CO when CO₂ absorbents are very dry (<5% water content); clinically important when circuits are left open with gas flow overnight.

---

---

PART 4: PHARMACODYNAMICS OF INHALATIONAL ANESTHETIC AGENTS

A. Mechanism of Action

1. Meyer-Overton Rule (Lipid Theory): Anesthetic potency correlates linearly (on log-log scale) with lipid solubility (oil:gas partition coefficient). Anesthetics dissolve in and perturb lipid membranes, altering membrane fluidity and ion channel function. However, this does not fully explain agent specificity or why some lipid-soluble drugs are not anesthetics.
2. Protein (Ion Channel) Theory: Modern evidence favors direct interaction with membrane proteins:
   • Potentiation of GABA-A receptors (Cl⁻ influx → hyperpolarization): shared mechanism with benzodiazepines/barbiturates; primary mechanism for most volatile agents.
   • Inhibition of NMDA receptors (glutamate antagonism): nitrous oxide, ketamine; contributes to analgesia and amnesia.
   • Potentiation of glycine receptors: contributes to immobility.
   • Inhibition of nicotinic ACh receptors.
   • Modulation of two-pore domain K⁺ channels (TREK-1/TASK): contribute to hyperpolarization.
3. Multi-site unitary theory: Anesthesia results from simultaneous actions at multiple molecular sites, with no single target sufficient to explain all components of the anesthetic state.

---

B. Minimum Alveolar Concentration (MAC)

MAC = Alveolar concentration of anesthetic (at 1 atm, in vol%) that prevents movement in response to a surgical skin incision in 50% of patients.

• Analogous to ED50 for IV drugs.
• Lower MAC = greater potency.
• Measured at steady state (alveolar = arterial = brain concentration).

MAC Variants

Factors Affecting MAC

• Increasing age (↓ ~6% per decade)
• Pregnancy (↓ ~30-40%)
• Hypothermia (↓ ~5-7% per °C below 37°C)
• Hypotension (MAP <40 mmHg)
• Severe anemia (Hgb <4 g/dL)
• CNS depressants (opioids, benzodiazepines, α2-agonists, N₂O)
• Hypothyroidism
• Lithium, methyldopa, reserpine (catecholamine depletion)
• Acute alcohol intoxication

• Young age
• Hyperthermia
• Chronic alcohol abuse
• CNS stimulants (cocaine, amphetamines - catecholamine release)
• Hyperthyroidism
• Anxiety/stress

• Duration of anesthesia
• PaO₂ (unless very low)
• Gender
• Hypo/hypercarbia (moderate ranges)
• Anesthesia type (spinal/epidural)

---

C. CNS Effects

• Dose-dependent CNS depression: Produces amnesia (0.25 MAC) → sedation → hypnosis → anesthesia → CNS isoelectricity (2+ MAC).
• EEG: Progressive burst suppression with increasing dose. Isoelectricity achievable with desflurane (uniquely reverts to continuous activity despite constant MAC - a property unique to desflurane).
• CMRO₂: All volatile agents decrease cerebral metabolic rate for O₂ in a dose-dependent manner.
• Cerebral blood flow (CBF): All potent agents increase CBF in a dose-related manner by direct cerebral vasodilation. Isoflurane, sevoflurane, desflurane cause less cerebral vasodilation per MAC-multiple than halothane.
  • At <1.5 MAC: sevoflurane and desflurane have minimal effect on CBF.
  • Phenomenon of "uncoupling": CMRO₂ falls but CBF rises → net vasodilation → potential ↑ ICP in patients with intracranial mass lesions.
  • Hypocapnia can blunt or abolish volatile anesthetic-induced increases in CBF.
• Autoregulation: Impaired by volatile agents in a dose-dependent manner (cerebral autoregulation curve shifts and may be abolished at >2 MAC).
• Seizures: Sevoflurane at high doses (1.5-2 MAC) with hypocapnia may provoke EEG abnormalities; clinical significance uncertain. Enflurane is the most clearly epileptogenic of the halogenated agents.

---

D. Cardiovascular Effects

• ↓ Blood pressure: Via ↓ myocardial contractility + ↓ SVR (vasodilation)
• ↓ Cardiac output: Isoflurane > desflurane/sevoflurane in direct myocardial depression at equivalent MAC
• ↓ SVR: Isoflurane and desflurane more than halothane
• Heart rate: Isoflurane and desflurane tend to maintain or mildly increase HR; halothane may cause bradycardia
• Desflurane: Rapid increase in inspired concentration → transient tachycardia and hypertension due to sympathetic stimulation (reflex from rapid rate of rise)
• Arrhythmias: Halothane sensitizes the myocardium to catecholamine-induced arrhythmias (most important); this is much less with isoflurane/sevoflurane/desflurane
• Myocardial protection: Volatile agents can produce ischemic preconditioning (protection against ischemia-reperfusion injury via KATP channels)

---

E. Respiratory Effects

• ↓ Tidal volume with compensatory ↑ respiratory rate (net: ↓ minute ventilation → ↑ PaCO₂)
• ↓ Ventilatory response to hypercapnia and hypoxia (blunts peripheral and central chemoreceptors)
• Airway smooth muscle relaxation → bronchodilation (useful in asthmatic patients)
• ↑ Airway secretions: Halothane, ether (less with modern agents)
• Airway irritation: Desflurane is most pungent (avoids inhalation induction); isoflurane intermediate; sevoflurane is least irritating (preferred for inhalation induction, especially in children)

---

F. Other Organ Effects

• Modern agents (isoflurane, sevoflurane, desflurane): minimal hepatotoxicity; may afford some cytoprotection against ischemic injury.
• Halothane hepatitis: Rare (1:20,000-35,000) immune-mediated fulminant hepatic necrosis from trifluoroacetyl hapten formation; can be fatal. Cross-sensitivity possible with other halogenated agents.

• Fluoride ions from metabolism of methoxyflurane (withdrawn) and enflurane caused nephrotoxicity (high-output renal failure). Sevoflurane metabolism produces fluoride ions but clinical nephrotoxicity is rare because sevoflurane's metabolism is rapid and brief.
• Compound A from sevoflurane + desiccated absorbent: nephrotoxic in animals; low-flow (<2 L/min) sevoflurane use remains a theoretical concern in humans.

• All volatile agents potentiate non-depolarizing neuromuscular blockers (reduce required doses).
• Malignant hyperthermia (MH): All volatile agents (and succinylcholine) are potent triggers in genetically susceptible patients (RYR1 mutation → uncontrolled calcium release from sarcoplasmic reticulum → hyperthermia, rigidity, acidosis). Treated with dantrolene.

• All volatile agents relax uterine smooth muscle in a dose-dependent manner → risk of uterine atony and hemorrhage. Limit to <0.5 MAC during obstetric procedures.

• Volatile anesthetics have global warming potential far exceeding CO₂. Desflurane has the highest warming potential; delivery with lower fresh gas flows reduces environmental impact.

---

Summary Comparison of Common Inhalational Agents

---

• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - Ch. 18 (Inhalational Anesthetics)
• Lippincott Illustrated Reviews: Pharmacology - Ch. 1 (Pharmacokinetics) & Ch. 2 (Pharmacodynamics)
• Katzung's Basic and Clinical Pharmacology, 16e - Ch. on General PK/PD principles