Pharmacokinetics Flashcards
Absorption
Movement of drug from site of administration to bloodstream
Factors affecting Absorption
Concentration gradient, size (<1 kDA), lipid solubility/membrane permeability
Charged drug
Hydrophilic and cannot diffuse
Uncharged drug
hydrophobic, passive diffusion
Which route of administration is not absorption?
Intravenous (IV)
Distribution
Reversible movement of drug from bloodstream to tissues
Factors affecting distribution
Concentration gradient, size (<1 kDA), lipid solubility/membrane permeability
Blood flow, protein binding
Blood flow and order (high –> low conc.)
Drug is delivered to tissues in relation to perfusion:
heart, liver, kidneys, brain –>muscles, skin, –> fat
Protein binding and example
Drugs bind reversibly to plasma proteins
Ex. albumin
What is the effect of protein binding?
Sequester (trap) drug in blood –> can’t distribute to target receptors, becomes pharmacologically inactive
decrease [free drug] = decrease therapeutic effect
Volume of distribution (Vd)
Relates amount of drug in body to its concentration in the blood
What does a large Vd mean (>42L)
drug distributes outside blood and body fluids into tissues/fat
What does a small Vd mean (<42 L)
drug has limited distribution, typically restricted to blood or physiological fluid components
Volume of Intracellular fluid (ICF)
28L
Volume of Extracellular fluid (ECF)
14L
Volume of Interstitial fluid
11L
Volume of Plasma
3L
Metabolism and its objective
Conversion of parent drug to metabolite(s), prepare drug for excetion
How and where does metabolism occur?
primarily in liver via 2 enzyme-catalyzed processes
Phase 1 of metabolism
Oxidation/reduction/hydrolysis
P450 enzymes add new or uncover existing polar group = increase H2O solubility
P450 enzyme inducers
increase enzyme activity = metabolism speeds up
What effect does a drug + inducer have?
Increase P450 = increase metabolic rate
subtherapeutic response
P450 enzyme inhibitors
decrease enzyme activity = metabolism slows down
What effect does a drug + inhibitor have?
Decrease enzyme activity = decrease metabolism
toxicity (drug accumulates in body)
Phase 2 metabolism
Non-P450 enzymes covalently add large, polar, endogenous molecules to Phase 1 metabolite or parent drug
What effect does Phase 2 have?
Change in structure + large = can’t fit into receptor
Polar = hydrophillic, prone to excretion
Prodrugs
Inactive drugs that become pharmacologically active after metabolism
Kidney excretion results in?
Irreversible loss of drug from body
What are the 2 primary routes of drug excretion?
- Passive glomerular filtration
- Active tubular secretion
Passive glomerular filtration
Small drugs passively diffuse from blood to kidney
Active tubular secretion
Large drugs actively transported by protein carriers from blood to kidney
Passive tubular reabsorption
Small/hydrophobic drugs with high concentration reabsorbed from kidney to blood, depends on urine pH
Excretion with bile
Drugs actively secreted from liver to intestine via common bile duct
What does it mean for bile excretion to be an active process?
Carrier mediated, not limited by size, protein binding, or ionization
Why are some areas of the lines of different routes of administration on a C vs T graph parallel?
Same drug = same distribution, metabolism, and excretion.
Only difference is absorption
How can you tell which line represents oral and IV administration on a C v.s. T graph?
IV: Cmax is at t=0 because it is instantaneous
MEC
Minimum effective concentration of a drug
Therapeutic Range
Concentration range between MEC and MTC, range where drug is considered effective and safe
MTC
Minimum toxic concentration of a drug. If [drug]>MTC -> toxic effects
Elimination Half-life (t1/2)
Time required for drug concentration to decrease by one half (50%)
Drug washout
Time required for a drug to be completely eliminated from the body (approximately 5 half-lives)
Repeat dosing
Administration of multiple doses of a drug over time
Peak and trough
Maximum and minimum drug concentrations in the body
Steady state
Rate of drug elimination equals rate of drug administration
Passive approach
Reaching steady state by giving repeated doses over 5 half-lives
Active approach
Reaching steady state by giving a loading dose
Loading Dose (LD)
Single large dose to quickly raise plasma drug concentration to therapeutic level
Maintenance Dose (MD)
Smaller doses given at intervals to maintain steady state
Vd
Volume of distribution of a drug
How do we calculate LD for IV administration?
Same equation except F=1 (bioavailability = 100%)
