Dd - Pk Absorption And Distribution

Front 1

Passive diffusion

Back 1

driven by concentration gradient

• Aqueous: have to go through channels or pores, which means they generally have to be really small.
• Lipid: often pH dependent (nonionized lipid-soluble drugs diffuse much better than ionized lipid-solubles).
 Lipid passive diffusion is the major route of drug delivery.

Front 2

major route of drug delivery

Back 2

lipid passive diffusion

Front 3

Carrier-mediated diffusion

Back 3

(drugs must resemble endogenous compounds for this to work)
• Facilitated diffusion (no energy requirement, driven by concentration gradient)
• Active transport (energy requirement, can move against concentration gradient)

Front 4

Explain the influence of pH on the ionization of weak acid/weak base drugs.

Back 4

ionized drugs can't cross membranes well, and pH influences ionization status.
o Notice that most weak acid drugs are weak acids due to a carboxyl (COOH-) group; most weak base drugs are weak bases due to an amine (NH3) group.

Front 5

• Use the Henderson-Hasselbeck equation to qualitatively predict the ratio of ionized to unionized species of a weak acid or weak base drug in various body compartments.

Back 5

pH = pKa + log ([A-/HA])

if pH is below pKa with an acid drug, it's predominantly nonionized. If pH is below pKa with a basic drug, it's ionized.

Front 6

weak acids are better absorbed in

Back 6

the small intestine, even though H-H principles would lead you to believe stomach

Front 7

H-H equation and absorption

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weak acids are trapped (in the nonabsorbable, ionized form) in more basic solutions; weak bases are trapped in more acidic solutions. Essentially drugs like to be absorbed on their 'home turf'-- acids absorb better in acid, bases absorb better in base.

Front 8

Enteral (oral/rectal)

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this blood always goes straight through the liver, which subjects it to first-pass metabolism and considerably lowers the effectively dose. Though it's easier, cheaper, safer, and usually more convenient, the bioavailability of enteral administration goes way down on account of the liver metabolism.

Front 9

routes of drug administration

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enteral

parenteral

Front 10

Parenteral (every other systemic route):

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generally less easy, less cheap, more dangerous, but higher bioavailability and faster effect.
• [minor] Localized/topical: administered directly to the tissue of action to avoid systemic effects.

Front 11

Oral

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slow to moderate onset, bioavailability ranges from 0-100%.
 Most common; most drugs are small, stable to low pH and digestive enzymes, and lipid-soluble.
 Notice most oral drugs are absorbed in the small intestine-- this means that anything that slows gastric emptying is going to slow oral drug absorption, which is why you should eat something before binge drinking (you know who you are).
 Notice also that the formulation of the drug - what the drug is encapsulated in - can be designed to break apart more quickly or more slowly to deliver a drug at particular rates.
• Enteric coating: a coating for a drug that doesn't dissolve until it reaches higher-pH environment- this means it won't deliver the drugs until it reaches the small intestine. This can protect the stomach lining from the drug and the drug from the stomach's pH.

Front 12

Rectal:

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slow onset, variable bioavailability. Usually used when patient is unconscious or vomiting.

Front 13

Sublingual

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Uptake into the caval venous system without going through the portal system (bypassing first-pass effect); don't need to use needles as per IV. High bioavailability and relatively rapid onset. Best with high-potency drugs.

Front 14

Intravenous:

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Very rapid onset (5-10 minutes); bioavailability, by definition, is 100%.

Front 15

Intramuscular:

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Slower, from slightly to much, onset than IV, depending on nature of drug. Close to 100% bioavailability.
 IM drugs given as aqueous solution leads to near-immediate onset.
 IM given as lipid solution can take days, weeks, or months to dissolve into the bloodstream. This gives a kind of timed, steady-release mechanism.

Front 16

Subcutaneous:

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Similar to IM, often used to get steady-state administration. Examples: Depo-Provera shots and NPH insulin.

Front 17

Inhaled:

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Can be topical (see below) or systemic. If the inhalant is a volatile gas, its effects will be systemic (can go to brain). If the inhalant is particles (ie. liquid droplets), its effects will be topical (throat and lungs only).
 Notice that even topical inhalants are often, if fractionally, distributed systemically.
 Notice also, not coincidentally, that most (close to 90%) of an inhaled drug is actually swallowed instead of inhaled.
 Onset of systemic inhaled drugs is extremely rapid, even moreso than IV route.

Front 18

Topical:

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Drug is put at its site of action and isn't dependent on circulation to have the desired effect. Eg.: local anesthetics.
 You generally want to use compounds that are readily metabolized, to protect against accidental systemic effects from topical drugs.

Front 19

Transdermal:

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Drug is put on skin; releases drug slowly into the systemic circulation (ie nicotine patches). Increases compliance (no missed doses).

Front 20

Explain the therapeutic consequences of "barriers" to distribution and selective accumulation of drugs.

Back 20

o To get from bloodstream to tissues, there is some dependence on the structure of the capillaries of those tissues.
• In the peripheral system, there are generally large gaps between adjacent endothelial cells which allow free drug to get into or out of the surrounding tissues (although not protein-bound drug-- it's too big).
• In the brain, the endothelial cells are tightly sealed together (blood-brain barrier) so that this leakage is not possible.
o At the placental border, there's some barrier action as well. Good rule of thumb is that if a drug can get into the bloodstream from oral administration (small, nonionized, lipid-soluble), it can get into both the brain and the fetus.
• This is why you use heparin in pregnant women and not warfarin-- heparin is IV administered and won't affect the fetus, warfarin is orally administered and will.
o Another barrier is in the kidneys-- after being taken up (filtered) by the glomerulus, to get back into the bloodstream it has to pass through the tubule membranes.

Front 21

Bioavailability

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o Bioavailability (F): what percentage of a given drug dose winds up in the blood.
This depends on the absorption of the drug across membranes. By definition, IV administration of a drug has a bioavailability of 100%, and every other route of administration has a smaller bioavailability.
• Notice that this means that bioavailability is the way to convert from oral to IV administration-- a 5 mg drug at 10% bioavailability orally equates to a .5 mg drug given intravenously. Important for avoiding overdose, etc.
 Ie: dose at IV divided by bioavailability for a different route of administration = dose for that alternate route.
• Note that bioavailability for a given drug for a given route of administration is calculated by comparing the plasma concentration-vs-time graph for that route vs. the IV route graph (defined as 100%). Essentially you divide the area under the curve of the route you're looking at by the area under the curve for IV administration.
• Note also that F only measures how much drug absorption takes place; the rate at which absorption takes place is the time to the peak plasma concentration.

Front 22

Adjustment of dose for oral vs parenteral administration:

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Drugs given orally have to pass through the liver to get to the bloodstream, which means they get hit by first-pass metabolism, which will oxidize and/or otherwise conjugate a significant fraction of the administered drug. What this means is that parenteral (non-oral) administration of drugs can have a smaller dose than per orem drugs because they're not subject to first-pass metabolism.
• That is to say: if you're looking at your dosages and you've got a oral dose that's lower than your IV dose, you've screwed the pooch in there somewhere, so go back and check your figures.

Front 23

Volume of Distribution (Vd):

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The consideration of the volume of the tissues or fluids into which the drug is going to wind up. This is significant because the final concentration of drug at its site of action is dependent on it. Dr. French advises looking at this as a dilution factor-- it's the factor which, combined with the dose of the drug, is going to give the eventual plasma concentration, which in turn is going to give the clinical effect. Got it?
• Notice here that the Vd parameter is usually only important with the loading dose; after this, the drug has been distributed to all the volume it's going to get to and no longer needs a dilution factor.

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Measuring Vd:

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 Vd is measured in terms of L/kg.
 After a given dose is administered by IV, the plasma concentration begins very high and initially drops precipitously: this is the distribution phase, in which the drug is being distributed to all the tissues and other fluids that it can get to.
 After a bit, the concentration begins to drop at a steady, lower rate; this is the elimination phase, in which the drug is actively being excreted from the body but has finished distributing.
 From the rate of elimination in the elimination phase, you can back-calculate the initial concentration (Cpo) that would have been required to maintain that rate of excretion had there been no need to distribute into tissues; from this, can calculate the volume into which the drug has to distribute before the distribution phase was over (ie., Vd).
• Vd = initial dose / Cpo
 Some things to keep in mind: if the Cpo is much lower than the initially administered dose, then it had a large volume into which to go. And if a drug had a large volume into which it went, it's probably pretty lipid-soluble to be able to get out of the plasma into the tissues.
• Dr. French sez: if a drug's Vd is about 40 L, that means it's in all the extra- and intra-cellular fluids in the body. If it's about 15 L, that means it's in all the extracellular fluids. If it's about 3 L, it's staying put in the plasma. If it's more than 40 L, it's getting into subcellular compartments of peripheral tissues.
 Notice that volume of distribution can include just about everything: brain, mucus, muscle, whatever. It's limited only by the size of your body and the solubility of your drug.
 Here's something else to think about that's easy to forget: plasma itself has a volume of distribution. There's roughly 3L of plasma in the average (nonexistent) human-- thus a volume of distribution of 3L indicates that a drug is trapped entirely in the plasma.

Front 25

Selecting loading dose

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implications of high or low values: This is mainly dependent on Vd-- you'd like to fill up the volume of distribution immediately so as to reach the steady-state plasma concentration that much quicker. High loading doses imply that there's a large volume of distribution to get through; low loading doses imply that the drug has a relatively restricted volume of distribution.