Absorption and Distribution

Question 1

Identify the factors that determine a given drug’s ability to cross biological membranes.

Answer 1

Size, lipid soubility, ionization, concentration gradient

Question 2

Describe the mechanisms by which drugs cross biological membranes (diffusion, transport, etc.).

Answer 2

Passive: driven by conc gradient
- If aqueous, depends on channel size (drug must be small, mw 100-200)
- If lipid diffusion, drug must be uncharged (pH dependent). Favored if drug has high lipid:water partition coeff
Carrier-mediated: transporter pumps in structurally similar molecules
Receptor-mediated endocytosis
Exocytosis of neurotransmitters

Question 3

Rate various ROAs with respect to BIOAVAILABILITY

Answer 3

100%: IV
75-100%: IM, subcut, sublingual, inhalation, transdermal (bioavailability approaches 100% as tissue environment non-destructive to most drugs)
0-100%: Oral. Varies due to GI environment or 1st pass effect metabolic effect

Question 4

Rate various ROAs with respect to SPEED OF ONSET

Answer 4

Fastest (sec-min): Inhalational, IV
Intermediate (5-15 min): Sublingual, intramuscular, subcutaneous, buccal
Slower (15-30 min): Oral - immediate release formulations
Slowest (hours): Transdermal, Oral - enteric-coated and sustained release formulations, IM and SC (depot forms)

Question 5

Explain the therapeutic consequences of anatomic “barriers” to distribution and selective accumulation of drugs.

Answer 5

To get from bloodstream to tissues, there is some dependence on the structure of the capillaries of those tissues.
In the peripheral system: large gaps between adjacent endothelial cells allowing 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 (BBB) so that this leakage is not possible.
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.
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.

Question 6

Describe how drug binding to plasma proteins can effect drug distribution and elimination as well as be a potential source of drug-drug interactions.

Answer 6

only free drug is diffusible
Acidic drugs bind primarily to albumin, basic drugs to alpha-1 acid glycoprotein.
• Reduces concentration of active, free drug
• Hinders metabolic degradation and reduce rate of excretion - i.e., acts as circulating drug reservoir that can prolong drug action
• Decreases volume of distribution by enhancing apparent solubility in blood
• Decreases ability to enter CNS across blood brain barrier
• Displacement drug-drug interactions (bumps off an old drug, which now might cause probe)

Question 7

Summarize the GENERAL therapeutic advantages and disadvantages of the various routes of drug administration, especially with regards to bioavailability and rate of onset of effect.

Answer 7

General types of routes:
Enteral (oral/rectal): straight through the liver = first-pass metabolism –> lowers the effective 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.
Parenteral: 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.

Question 8

Advantages & disadvantages of oral route

Answer 8

Oral: 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

Enteric coating: doesn’t dissolve until it reaches higher-pH environment of small intestine. This can protect the stomach lining from the drug and vice versa

Question 9

Advantages & disadvantages of rectal route

Answer 9

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

Question 10

Advantages & disadvantages of sublingual route

Answer 10

Sublingual: Uptake into the cavalvenous 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.

Question 11

Advantages & disadvantages of IV

Answer 11

Intravenous: Very rapid onset (5-10 minutes); bioavailability, by definition, is 100%.
Intramuscular: Slower, from slightly to much, onset than IV, depending on nature of drug. Close to 100% bioavailability.

Question 12

Advantages & disadvantages of IM/SC

Answer 12

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

Question 13

Advantages & disadvantages of Inhalation

Answer 13

Inhaled: 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.

Question 14

Advantages & disadvantages of topical

Answer 14

Topical: 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.

Question 15

Advantages & disadvantages of transdermal

Answer 15

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

Question 16

Explain bioavailability

Answer 16

% of a given drug dose winds up in the blood; depends on the absorption of the drug across membranes.

Calculated by making graph of Cp vs time and divide the AUC for specific ROA by AUC for IV.

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.

Question 17

Adjustment of dose for oral vs parenteral administration:

Answer 17

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 oral drugs because they’re not subject to first-pass metabolism.

Question 18

Volume of Distribution (Vd):

Answer 18

Vd = 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.

Think of it as 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. (note: usually only important w/ loading dose)

Vd is measured in terms of L/kg.
Admister drug, Cp shoots up (distribution phase) then is eliminated linearly. From here, back calc the initial Cp 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

IF the Cpo is much lower than the initially administered dose, then it had a large volume into which to go, so it’s probably pretty lipid-soluble to be able to get out of the plasma into the tissues.
3 L = stay in plasma
15 L = All the EC fluids
40 L = it’s in all the EC & IC fluids
>40 = it’s getting into subcellular compartments of peripheral tissues.

Vd = EVERYTHING (brain, mucus, muscle)

Question 19

Loading dose implications of high & low values

Answer 19

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.