Pharmacokinetics Flashcards
Pharmacokinetics
how drugs enter & leave the body; plasma drug concentrations vs time; what the body does to a drug, and how to avoid complications. Aka ADME
ADME
Absorption from site of administration, Distribution within the body, Metabolism, Excretion
Systemic drug administration
Given into blood. Needs to act at inaccessible site.
Local drug administration
Given direct to site of action. E.g. local anaesthetic
Oral administration
<100%. Depends on solubility; drug pKa, pH of GI tract; stability (acid may destroy); gastric emptying and GI motility (mostly absorbed in upper GI; emptying slowed by food; motility depends on drugs and disease); GI blood flow; First pass effect (can get lost in hepatic portal vein before reaching systemic circulation)
First pass effect
Most of GI tract goes through hepatic portal vein to liver, so drug can be metabolized before reaching systemic circulation.
Bioavailability
% of dose reaching systemic circulation. Loss loss due to metabolism or excretion; direct effect on therapeutic outcome; different for different formulations; may vary with liver function
Advantage of oral route
No need for drug to be pure or sterile; easy for patient, no pain - most common; cheap formulations, multi-dose bottles
Disadvantage of oral route
Requires conscious, cooperative patient; slow, so no good for emergencies; variable absorption and bioavailability; loss of drug if patient vomits; potential for upper GI tract irritation (less damage if accompanied with food)
Rectal administration
Obvious! fairly rapid absorption possible; less first-pass effect.
Pros and cons of rectal
Good for patients who cannot swallow (unconscious); won’t swallow (children, psychotics); may be vomiting. Mildly inconvenient.
Parenteral route
Means not via enteral route (ie not between glottis and anus), but not only injection
Sulbligual
direct entry to systemic circ. (no first pass); rapid absorption possible despite low area; pH about 7 so acid-labile drugs are stable; fast, easy, comfortable
IV
Can be rapid (IV push) or slow (IV drip or infusion) - concentration can increase quickly or gradually; acts quickly. Need skill to find veins; drug cannot cause pain or damage; need sterile solutions; greater risk and cost
Other routes of administration
subcutaneous, vaginal, intramuscular, intracardiac, urethral, transdermal, inhalation, topical, intranasal, intrathecal, spinal, buccal, intra-articular, occular
Drug distribution
Depends on solubility of drug in fat or tissue; pH of compartment and pKa of drug (effect of charge); plasma protein binding. this can affect the duration of action or how long the drug stays in body. Needs to be unbound and free for diffusion across membranes; binding to receptors and enzymes; hepatic metabolism and renal filtration
Termination of drug effects
Biotransformation aka metabolism. Body wants to make it more polar Phase I: drug made more polar by cytochrome P450 enzyme families (CYPs) - change to drug; Phase II: drug conjugation to endogenous compounds from liver, so the addition makes it more polar
Where does drug metabolism occur?
most occurs in the liver; may also occur in kidneys, gut, lungs, plasma and placenta; polar products undergo renal elimination
Drug metabolites
may be many for a single drug; usually most are inactive; rarely have biological activity; more rarely, an inactive drug (called a “pro-drug”) may be activated by metabolism
What can affect metabolic rate?
Can be increased or decreased by age, disease, genetics, diet, tobacco, alcohol, other meds
How are drugs excreted?
Kidney: can be affected by kidney disease, renal blood flow, MW urinary pH, protein binding. Gall bladder: may get secreted from liver into bile; some drug reabsorption from bile in gut; termed enterohepatic circulation
First order elimination
constant proportion lost per unit time. Proportional to the concentration. Straight line on a log graph. Easy calculations for initial conc. and t1/2. Drug is accepted as “gone” after 4 or 5 t1/2
Zero order elimination
Less common. Constant amount lost per unit time. Straight line on a normal linear graph, nosedive on log scale. Often after enzymes are saturated. Classic example is ethanol.
What effect does doubling the dose have for a first order drug?
It does NOT double the duration. It increases duration by one half the time, or by 50%. (think of it, half-life)
Volume of distribution, Vd
Volume in which drug “seems” to be dissolved. If 10 mg is given via IV, and [plasma] .25mg/L, the Vd is 40L. Larger Vd indicates lots of drug binding so very little free in plasma. Vd affected by gender, age, disease. [plasma] = drug dose/Vd
Drug clearance, CL
volume/unit time. volume refers to volume of plasma cleared of drug. CL is additive, so renal + hepatic + other
Compartment models
Single: consider body as one box that it goes in and out of. 2 compartment: 2 boxes. Into one then into a second one or cleared directly from first; two phases of elimination: a is quick initially, then ß is slower
Multiple drug dosing
Need to maintain therapeutic conc. Either increase dose (toxic?) or reduce dosing interval so you reach an equilibrium usually in 4-5 t1/2
Loading dose
Decreases time to plateau. Best is loading dose plus continuous infusion. Reaches plateau fast and stays there
