Pharmacology
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Explain how drug pharmacokinetics works
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I now have everything needed for a thorough, well-illustrated answer. Here it is:
Drug Pharmacokinetics: How the Body Handles a Drug
Pharmacokinetics (PK) is the study of what the body does to a drug - tracking it from the moment of administration until it leaves the body. There are four sequential processes, remembered as ADME: Absorption, Distribution, Metabolism, and Elimination.
Figure 1.1 from Lippincott Illustrated Reviews: Pharmacology - the full ADME cycle
1. Absorption
Absorption is the movement of a drug from its site of administration into the bloodstream (plasma).
Key factors affecting absorption:
| Factor | Effect |
|---|---|
| Drug ionization (pKa) | Only the uncharged (nonionized) form crosses lipid membranes. Weak acids are better absorbed in the acidic stomach; weak bases in the alkaline intestine. |
| Lipid solubility | More lipophilic drugs cross membranes more easily. |
| Blood flow | Intestines receive far more blood than the stomach - intestinal absorption dominates. |
| Surface area | The intestine's brush border gives it ~1000x more surface area than the stomach. |
| Contact time | Diarrhea speeds transit, reducing absorption; food delays gastric emptying and slows absorption. |
| P-glycoprotein | A transporter that "pumps" drugs back out of cells; high expression (gut, liver, brain) reduces absorption and contributes to multidrug resistance. |
Bioavailability (F)
Bioavailability is the fraction of an administered dose that reaches systemic circulation unchanged. IV administration = 100% bioavailability by definition. Oral bioavailability is often lower due to:
- Incomplete absorption from the GI tract
- First-pass effect: orally absorbed drugs go via the portal vein to the liver, where extensive hepatic metabolism can dramatically reduce the amount reaching systemic circulation (e.g., nitroglycerin has very low oral bioavailability but high sublingual bioavailability because it bypasses the liver).
Routes of Administration
Different routes affect the speed, extent, and site of absorption:
- IV - instant, 100% bioavailability, useful in emergencies
- Oral - convenient but subject to first-pass metabolism
- Sublingual - rapid; bypasses first-pass (e.g., nitroglycerin)
- Transdermal - slow, sustained; depends on skin lipid solubility
- Rectal - 50% bypasses portal circulation, useful if vomiting
- Inhalation - fast onset, directly to lung tissue
2. Distribution
After entering plasma, a drug distributes reversibly into tissues and body fluid compartments.
Protein Binding
- Drugs in plasma bind to albumin (the main carrier protein) and other plasma proteins.
- Only the free (unbound) drug is pharmacologically active, can cross membranes, and can be metabolized or excreted.
- Bound drug acts as a reservoir; as free drug is eliminated, bound drug dissociates to maintain a constant ratio.
Volume of Distribution (Vd)
Vd is a theoretical number expressing how widely a drug distributes:
Vd = Amount of drug in body / Plasma concentration (C₀)
| Vd | What it means | Example |
|---|---|---|
| ~4 L | Stays in plasma (large/highly protein-bound) | Heparin |
| ~14 L | Distributes into extracellular fluid | Aminoglycosides |
| ~42 L | Distributes into total body water | Ethanol |
| >100 L | Extensively sequestered in tissues | Chloroquine |
Lipophilicity and Compartments
- Lipophilic drugs easily cross cell membranes, distributed by blood flow, can enter the CNS.
- Hydrophilic drugs cannot cross cell membranes freely - they stay in plasma or extracellular fluid.
- The blood-brain barrier (tight junctions + P-glycoprotein) limits CNS entry to small lipophilic molecules.
3. Metabolism (Biotransformation)
Metabolism converts drugs (usually lipophilic) into more polar (water-soluble) metabolites for excretion. The liver is the primary site, but gut wall, lungs, kidneys, and plasma also contribute.
Phase I Reactions - "Functionalization"
Introduce or unmask a polar functional group (-OH, -NH₂, -SH).
- Primarily carried out by cytochrome P450 (CYP) enzymes (CYP3A4 is the most abundant, responsible for ~50% of drug metabolism).
- Reactions include oxidation, reduction, hydrolysis.
- Products may be active, inactive, or toxic.
CYP Inducers (increase drug metabolism → lower plasma levels):
Rifampin, carbamazepine, phenytoin, St. John's Wort
CYP Inhibitors (decrease drug metabolism → higher plasma levels, toxicity risk):
Ketoconazole, clarithromycin, ritonavir, omeprazole
Phase II Reactions - "Conjugation"
Attach an endogenous molecule to the drug or Phase I metabolite to make it more water-soluble:
- Glucuronidation (most common) - via UDP-glucuronosyltransferase
- Sulfation, acetylation, methylation, glutathione conjugation
Phase II metabolites are usually inactive and excreted readily. Notable exception: morphine-6-glucuronide is MORE potent than morphine itself.
Some drugs with existing -OH, -NH₂, or -COOH groups skip Phase I and go directly to Phase II.
4. Elimination
Drugs and metabolites leave the body primarily via kidneys (into urine) or liver (into bile/feces).
Renal Excretion
Three processes in the kidney:
- Glomerular filtration - free (unbound) drug is filtered at the glomerulus (GFR ~120 mL/min). Protein-bound drug is NOT filtered.
- Active tubular secretion - transporters (OAT, OCT) actively secrete drugs into the tubule, even protein-bound drug. This can be saturated or competitively inhibited.
- Passive tubular reabsorption - lipophilic drugs are reabsorbed from the tubule back into blood. Ionized (polar) drugs are trapped in urine and excreted. Urine pH manipulation exploits this (e.g., alkalinizing urine traps weak acids, speeding excretion in aspirin overdose).
Biliary/Fecal Excretion
Some drugs are secreted into bile and eliminated in feces. Enterohepatic recirculation (drug reabsorbed from gut back into blood) can prolong drug action.
Key PK Parameters
| Parameter | Definition | Clinical Relevance |
|---|---|---|
| Half-life (t½) | Time for plasma concentration to halve | Determines dosing interval; ~4-5 half-lives to reach steady state or full elimination |
| Clearance (CL) | Volume of plasma cleared of drug per unit time | Key determinant of maintenance dose |
| Vd | Apparent volume of distribution | Determines loading dose |
| Bioavailability (F) | Fraction reaching systemic circulation | Determines oral dose vs. IV dose |
| Steady state | When rate of drug in = rate out | Reached after ~4-5 half-lives of consistent dosing |
First-Order vs. Zero-Order Kinetics
- First-order: A constant fraction of drug is eliminated per unit time (most drugs). t½ is constant regardless of dose.
- Zero-order: A constant amount of drug is eliminated per unit time (saturable processes - e.g., ethanol, phenytoin at high doses). t½ increases with dose - dangerous accumulation can occur.
Summary
Administration → Absorption (into plasma)
↓
Distribution (to tissues)
↓
Metabolism (liver - Phase I & II)
↓
Elimination (kidney/bile)
Understanding ADME allows clinicians to rationally design dosing regimens, predict drug interactions, adjust doses in renal/hepatic impairment, and explain why the same dose affects patients differently.
- Lippincott Illustrated Reviews: Pharmacology, Ch. 1
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