Pharmacokinetics Lecture Notes

Comprehensive flashcards covering the key principles of pharmacokinetics, including absorption, distribution, metabolism, excretion (ADME), volume of distribution, bioavailability, enzyme induction/inhibition, and renal clearance dosing.

What are the four main stages that comprise pharmacokinetics (PK)?

Absorption, Distribution, Metabolism, and Excretion (ADME).

What key clinical dosing and administration parameters does pharmacokinetics determine?

What dose to give, how often to give it, how to adjust the dose in specific medical conditions, how many drug interactions occur, and which route of administration to use.

What three key variables influence drug absorption into the body?

The route of administration, the chemical properties of the drug, and the formulation of the drug.

Why do smaller-sized drug particles dissolve faster than larger particles?

Smaller-sized particles have a greater surface area-to-weight ratio.

What is the typical gastric emptying time for oral medications into the duodenum?

$1\text{--}5\,\text{hours}$.

What are the specific $\text{pH}$ levels and lengths of the small intestine sections?

The duodenum has a $\text{pH}$ of $5$, the ileum has a $\text{pH}$ of $8$ and is the longest section at $3\,\text{m}$, and the total small intestine measures $5.5\,\text{m}$ in length with a transit time of $2\text{--}6\,\text{hours}$.

What are the three primary mechanisms by which drugs cross the small intestine into the blood, and what is one less common mechanism?

The three main mechanisms are passive diffusion, facilitated diffusion, and active transport; a less common mechanism is pinocytosis.

How does drug ionisation influence absorption across biological membranes?

Unionised drugs are absorbed more readily, whereas ionised drugs are poorly absorbed. Acids become ionised in basic media, and bases become ionised in acidic media.

Where in the gastrointestinal tract are weak acids and weak bases predominantly absorbed?

Weak acids (e.g., aspirin and naproxen) are absorbed from the stomach, whereas weak bases (e.g., pethidine and diphenhydramine) are absorbed from the small intestine.

What anatomical route does an orally absorbed drug follow to enter the systemic circulation?

The drug crosses the gut wall, enters the hepatic portal circulation via the portal vein, travels to the liver, and exits through the hepatic vein to enter the systemic circulation.

How is drug bioavailability defined, and what factors influence it?

Bioavailability is the fraction of an administered dose reaching systemic circulation (as a percentage). It is influenced by the route of administration, drug formulation, presence of food/drugs in the GI tract, drug stability in the GI tract, and extent of first-pass metabolism.

What is first-pass metabolism?

The breakdown of an orally absorbed drug by liver enzymes after travelling through the hepatic portal vein, occurring before the drug reaches systemic circulation.

What is the oral bioavailability of vancomycin compared to its intravenous bioavailability?

Vancomycin has an oral bioavailability of $0\%$ and an intravenous bioavailability of $100\%$.

What are the oral bioavailabilities of ciprofloxacin, fluconazole, and amoxicillin?

Ciprofloxacin is $70\text{--}80\%$, fluconazole is $>90\%$, and amoxicillin is $70\%$ (each is $100\%$ intravenously).

How do high-fat and high-protein diets affect the absorption of orally administered drugs?

A high-fat diet can delay gastric emptying, whereas a high-protein diet may inhibit the absorption of drugs that utilise protein transporters.

Which specific carrier protein mediates the absorption of levodopa?

The phenylalanine carrier.

How do iron supplements interact with ciprofloxacin in the gastrointestinal tract?

Iron supplements bind to ciprofloxacin within the gut lumen, reducing its absorption.

What are the four major body compartments and four smaller compartments involved in drug distribution?

The four major compartments are blood (plasma), fat, intracellular fluid, and extracellular fluid. The smaller compartments are cerebrospinal fluid (CSF), peritoneum, synovial fluid (joints), and the fetus (in pregnancy).

How do lipophilic and hydrophilic drugs differ regarding membrane penetration, distribution, and primary clearance?

Lipophilic drugs exhibit good membrane penetration, distribute mainly into body fat, cross the blood-brain barrier, and undergo hepatic clearance. Hydrophilic drugs exhibit poor membrane penetration, distribute into body water, do not cross the blood-brain barrier, and undergo renal clearance.

What is the volume of distribution ($V_d$), and how does a high $V_d$ impact dosing?

$V_d$ is a theoretical value indicating the drug amount required in the body to produce a specific plasma concentration; a larger $V_d$ requires a larger dose to reach the target concentration.

What are the physiological fluid compartment volumes in a reference $65\,\text{kg}$ adult?

Total body water is $39\,\text{L}$, intracellular fluid is $26\,\text{L}$, interstitial fluid is $10\,\text{L}$, and plasma volume is $3.5\,\text{L}$.

What are the volumes of distribution ($V_d$) and characteristics for warfarin, theophylline, and diazepam?

Warfarin has a $V_d$ of $0.14\,\text{L/kg}$ (high protein binding, stays mostly in plasma); theophylline has a $V_d$ of $0.5\,\text{L/kg}$ (low protein binding, distributes in body water); diazepam has a $V_d$ of $2.4\,\text{L/kg}$ (high lipid solubility, distributes into tissues and fat).

At what percentage of plasma protein binding do alterations in protein levels become clinically significant?

When drugs are greater than $90\%$ bound to plasma proteins ($>90\%$).

Which medications are greater than $95\%$ bound to plasma proteins?

Levothyroxine, warfarin, diazepam, furosemide, and heparin.

Which medications have plasma protein binding between $90\%$ and $95\%$?

Glibenclamide, phenytoin, propranolol, sodium valproate, imipramine, and amitriptyline.

What clinical factors can increase the fraction of unbound (free) drug in plasma?

Low plasma albumin levels ($<20\text{--}25\,\text{g/L}$), late pregnancy (increased blood volume lowering albumin concentration), displacement by competing drugs, and saturation of protein-binding sites.

Why does the blood-brain barrier (BBB) exclude most pharmaceutical agents?

Due to very tight junctions between endothelial cells lining cerebral capillaries, allowing only select small lipophilic molecules or specially engineered drugs to cross.

What is the primary biochemical purpose of drug metabolism?

To chemically convert drugs into more hydrophilic (water-soluble) substances that can be readily excreted via the urine or bile.

How do Phase 1 and Phase 2 drug metabolism differ?

Phase 1 involves chemical changes such as oxidation, reduction, or hydrolysis (predominantly mediated by cytochrome P450 enzymes). Phase 2 involves conjugation with endogenous chemicals to produce an inactive, excretable compound.

Which specific cytochrome P450 enzyme is responsible for metabolising approximately $50\%$ of all medications?

CYP3A4.

How do enzyme-inducing drugs affect drug levels, and what is their typical induction time frame?

They accelerate enzyme synthesis, increasing drug clearance, reducing plasma concentration, and shortening half-life; maximum induction takes up to $14\,\text{days}$, and returning to baseline after withdrawal takes up to $14\,\text{days}$.

What are seven examples of hepatic enzyme inducers?

Phenytoin, phenobarbitone, carbamazepine, rifampicin, griseofulvin, chronic alcohol intake, and smoking (not nicotine).

How do enzyme inhibitors alter drug pharmacokinetics, and what is their onset timeline?

They directly block metabolising enzymes, decreasing clearance, elevating drug plasma levels, and extending half-life; they act immediately with no time delay and resolve once the inhibitor is cleared.

What are seven examples of hepatic enzyme inhibitors?

Erythromycin, ciprofloxacin, metronidazole, allopurinol, isoniazid, sodium valproate, and cimetidine.

Why is the oral dose of propranolol ($40\,\text{mg}$) significantly higher than its intravenous dose ($1\,\text{mg}$)?

A large proportion of an oral dose of propranolol is degraded by first-pass metabolism in the liver before it ever reaches the systemic circulation.

How are the terms elimination, excretion, and clearance differentiated?

Elimination encompasses all processes removing a drug from the body; excretion is the physical removal of waste products and metabolites (primarily via kidneys in urine, or via bile, lungs, and sweat); clearance is the volume of blood cleared of drug per unit time.

What are the standard physiological values for renal blood flow and glomerular filtration rate (GFR)?

Normal renal blood flow is $1500\,\text{mL/min}$, and normal glomerular filtration rate is $120\,\text{mL/min}$.

Which equation is used to calculate creatinine clearance, and in which populations is eGFR less reliable?

The Cockcroft-Gault Equation; eGFR is less reliable in the elderly (reduced muscle mass), children under $18$ (untested equation), and obese individuals (altered muscle-to-fat ratio).

What is drug half-life ($t_{1/2}$), and how can renal impairment impact digoxin's half-life?

Half-life is the time required for plasma drug concentration to decrease by half; in renal impairment, digoxin's half-life can exceed $100+\,\text{hours}$.

What dose adjustment is recommended for gabapentin in patients with a creatinine clearance of $15\text{--}29\,\text{mL/min}$?

Reduce dose to $150\text{--}600\,\text{mg}$ daily, administered in $3$ divided doses.

What is steady state in pharmacokinetics?

The state reached during regular dosing where the rate of drug absorption equals the rate of drug elimination ("amount in" equals "amount out").

What is the clinical rationale for administering a loading dose?

To rapidly achieve therapeutic plasma drug concentrations for drugs with a long elimination half-life (such as digoxin).

What is the therapeutic range of a drug?

The dosage concentration window between the minimum effective therapeutic concentration and the minimum toxic concentration.