Pharmacokinetics - Tumblr Posts
259 FA 12 : PHARMACOKINETICS EQUATIONS PART 1 (by 100lyric)
There’s a mistake with the formulas, is supposed to be:
Loading dose : (Vd x Cp)/F
Maintenance dose: (cl x Cp)/F
259 FA 12 : PHARMACOKINETICS EQUATIONS PART 1 (by 100lyric)
There’s a mistake with the formulas, is supposed to be:
Loading dose : (Vd x Cp)/F
Maintenance dose: (cl x Cp)/F
September 29, 2015 - more pharmacokinetics. I found out I made an A on my first exam in there!
Grapefruit Juice & Drug Metabolism
Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived.
To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6’,7’-dihydroxybergamottin, it is believed to be responsible for the grapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.
Pharmacokinetics Overview
(Absorption and distribution of drugs)
The study of the time course of drugs and their metabolites in the body (what the body does to the drug) consisting of:
administration
absorption
distribution
metabolism
excretion
Administration
Enteral (passes through intestine)
oral (mouth)
buccal/sublingual (applied in cheek/under tongue)
Gastrosomy (surgical opening through the abdomen into the stomach)
Topical (applied directly)
Nasal
Rectal
Ophthalmic (eyes)
Parentral (injection)
Intravenous (into veins)
intramuscular (into muscles)
intradermal (within layers of skin)
subcutaneous (under the skin)
Drug molecules move around the body either through bulk flow (bloodstream, lymphatics or cerebrospinal fluid) or diffusion (molecule by molecule over short distances)
Absorption
Passage of drug from its site of administration into plasma - important for all routes except intravenous injection.
Injection
IV = fastest route of administration
bolus injection = very high concentration of drug
rate limiting factors = diffusion through tissues and removal by local blood flow
Drugs need to pass through membranes (cell membranes, epithelial barriers, vascular endothelium, blood-brain barrier, placenta barrier etc) via
passive diffusion through lipids
carrier-mediated
passage through membrane pores/ion channels
pinocytosis (ingestion into a cell by the budding of small vesicles from the cell membrane)
Diffusion through lipid
non-polar molecules can dissolve freely in membrane lipids
the rate is determined by the permeability coefficient (P)(solubility in the membrane and diffusibility) and the concentration difference across the membrane
pH and Ionisation
Many drugs are weak acids or weak bases
exist in unionised or ionised forms
pH = balance between the two forms
ionised forms have low lipid solubility
uncharged however the drug is usually lipid soluble
ionisation affects:
rate of drug permeation through membranes
steady state distribution of drug molecules between aqueous compartments if pH difference exists between them
Therefore:
urinary acidification accelerates the excretion of weak bases and slows that of weak acids
alkalisation has opposite effect
increasing plasma pH causes weak acids to be extracted from CNS into plasma
Reducing plasma pH causes weakly acidic drugs to become concentrated in CNS, increasing neurotoxicity
Bioavailibility
Bioavailibility (F) indicates the fraction of an orally administered dose that reaches systemic circulation intact, taking into account both absorption and local metabolic degradation
determined by comparison between oral and IV absorption
affected by:
drug preparation
variation in enzyme activity of gut
gastric pH
intestinal motility
Volume of Distribution
Vd is defined as the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma, Cp
determined by relative strength of binding between drug and tissue compared with drug and plasma proteins
tight binding to tissue but not plasma –> drug appears to be dissolved in large volume –> large Vd (eg chloropromazine)
tight binding to plasma –> V can be very close to blood volume –> low Vd (eg warfarin)
PHARMACOKINETICS CALCULATIONS
Single-Dose: •Vd = Dose/Co •t1/2 = 0.7 x Vd/Cl
Multiple-Dose, Infusions: •Ko = Cl x Css •LD = Vd x Cp/f •MD = Cl x Css x dosing interval/f
Vd: volume of distribution Co: plasma [ ] at zero time Cp: plasma [ ] t1/2: half life Cl: clearance = free fraction x GFR Ko: infusion rate Css: steady state [ ] LD: loading dose MD: maintaining dose f: bioavailability
If someone has an 'enhanced metabolism' that processes drugs faster, is it easier or harder for them to overdose? Wouldn't they uptake more of a drug quicker, therefor making it more dangerous? I see this a lot with Captain America and Spider-man and such, where the dose of various medicines will be raised and I'm not sure that makes sense?
…oooooh you sure have opened a can of pharmacokinetic worms here….
Simply put, whether the drug never reaches therapeutic blood levels, or exceeds them, depends on 1) how the character’s metabolism works, and 2) what kind of drug they ingested (skip to the bolded part at the end of the post to get the tl;dr).
When you take a drug, the following happens (this process is sometimes denoted as “ADME” or “LADME”:
The drug must separate from the vehicle that brought it into the body (for example, a pill must disintegrate in the stomach, releasing the drug, or an IM or IV drug must separate from its solution): Liberation
The drug must be absorbed into the bloodstream (for a pill this would mean getting absorbed through the lining of the stomach or intestine, for IM injections this means getting absorbed by blood vessels running through the muscle where the drug is): Absorption
The drug must be deposited from the bloodstream into a location where it can be used: Distribution
The drug must be metabolized (broken down or changed by a biologic process, creating different chemicals called metabolites): Metabolism
The drug metabolites must be excreted from the body: Elimination
The first end of this process is largely driven by regular old chemistry. A pill has to dissolve to release the drug, and assuming that these characters have similar stomach/small intestine environments, this is not going to be different for them.
Absorption is mostly driven by a concentration gradient (substances like to be at the same concentration across membranes, so if there’s more drug in the small intestine than there is in the blood around the small intestine, the drug gets absorbed into the blood as the concentrations try to equalize), so this too is probably not going to be all that different. Even distribution is (mostly) driven by that concentration gradient, so, again, this process wouldn’t necessarily be any different from that of a normal human.
Now, the latter half of this process is a lot more dependent on a person’s specific physiology. When we talk about metabolism, we’re talking about how the body changes ingested chemicals into something excrete-able. For many drugs, this change involves enzymes in the liver.
About 6 different liver enzymes are responsible for the metabolism of about 90% of drugs. Each different enzyme is responsible for the breakdown of a different group of drugs.
Some people have genetic mutations that cause more or less of an enzyme to be produced. People who make more of an enzyme metabolize that group of drugs faster, while people who make less of them metabolize those drugs more slowly.
Through certain genetic tests, real life people can be designated one of the following for any given group of drugs:
Ultrarapid Metabolizers have the genetic wiring to produce way, way more copies of an enzyme than the typical person, and metabolize the corresponding drugs very, very quickly
Extentive Metabolizers produce more copies of the enzyme than most people
Intermediate Metabolizers produce an average number of copies
Poor Metabolizers produce significantly fewer copies than average, leaving them unable to metabolize the drugs normally
Now, remember how I said it also has to do with what kind of drug it is? There are two different kinds of drugs I’m talking about: Active Drugs and Prodrugs. Active drugs are able to be used by the body as-is. Prodrugs only have an effect once they’ve been metabolized by the body into a different substance.
Say someone is an ultrarapid metabolizer of an active drug. They take the drug, it gets absorbed and distributed like normal, but they rapidly metabolize it into inactive substances and excrete it. This person would either get no effect from a typical dose, or only a very slight one, because the drug is never allowed to build up to effective levels in their blood before getting metabolized.
But say that same person is a poor metabolizer of a different active drug. They take the drug, it gets absorbed, but they only very slowly are able to metabolize and excrete it. The drug ends up building up in their blood and staying there longer, possibly causing an overdose of the drug at a typical dose.
The situation would be reversed if the drugs were prodrugs instead. An ultrarapid metabolizer of a prodrug ends up metabolizing too much of the active substance too quickly, possibly causing overdose, while a poor metabolizer of a prodrug maybe never metabolize enough to get effective concentrations of the end substance (check out this post on the prodrug codeine).
Finally, applying this real-life precedent to Captain America, or Flash, or Spider-Man canon evidence, you would have to assume that due to their respective super powers, they all produce a metric sh*tton of liver enzymes capable of metabolizing drugs super fast and hella effective kidneys for excreting them. Typical doses of active drugs would barely work on them, while prodrugs might have a short, but incredibly strong effect on them.
R E F E R E N C E S