Editing Pharmacology (section)

== Core Concepts: Pharmacokinetics and Pharmacodynamics ==

'''Pharmacokinetics''' is what the body does to the drug. Four phases:

* '''Absorption''': movement of drug from the site of administration into the bloodstream. Intravenous drugs bypass absorption entirely and are 100 percent bioavailable. Oral drugs are the slowest and most variable. Food, gastric pH, and gut motility all change absorption.
* '''Distribution''': movement of drug from blood into tissues. Affected by blood flow, protein binding, and lipid solubility. Only the '''free (unbound)''' fraction is pharmacologically active. In low albumin states such as malnutrition, liver disease, or nephrotic syndrome, more free drug circulates and toxicity can occur at "normal" doses. Highly protein bound drugs such as warfarin and phenytoin compete for binding sites and can displace one another.
* '''Metabolism (biotransformation)''': primarily hepatic, largely by the cytochrome P450 enzyme system. '''Enzyme inducers''' (rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) speed metabolism and '''lower''' serum levels of other drugs. '''Enzyme inhibitors''' (many azole antifungals, macrolides such as erythromycin and clarithromycin, grapefruit juice, some protease inhibitors) slow metabolism and '''raise''' levels, increasing toxicity risk.
* '''Excretion''': primarily renal. Declining creatinine clearance means drug accumulation. Always check renal function before nephrotoxic or renally cleared drugs (aminoglycosides, vancomycin, digoxin, metformin, lithium, many direct oral anticoagulants).

'''First-pass effect''': oral drugs absorbed from the gut travel through the portal vein to the liver and may be substantially metabolized before reaching systemic circulation. This is why sublingual, buccal, transdermal, rectal, and parenteral routes produce higher bioavailability and why the oral dose of a drug such as morphine is much larger than the intravenous dose.

'''Half-life''' is the time for serum concentration to fall by 50 percent. It takes roughly four to five half-lives to reach '''steady state''' on a fixed schedule, and roughly four to five half-lives to clear a drug after it is stopped. This explains why antidepressant effects take weeks and why a loading dose is used when a rapid therapeutic level is needed.

'''Pharmacodynamics''' is what the drug does to the body.

* '''Agonist''': binds a receptor and produces the response (albuterol at beta-2 receptors).
* '''Antagonist''': binds a receptor and blocks the response (naloxone at opioid receptors, metoprolol at beta-1 receptors).
* '''Partial agonist''': produces a submaximal response (buprenorphine).
* '''Therapeutic index''': the ratio of toxic dose to therapeutic dose. A '''narrow''' therapeutic index means small dosing changes cause toxicity, so serum levels are monitored. Classic examples: digoxin, lithium, phenytoin, theophylline, warfarin, vancomycin, aminoglycosides.
* '''Peak and trough''': the peak is the highest serum concentration and reflects toxicity risk; the trough is drawn immediately '''before''' the next dose and reflects whether the level is staying therapeutic.