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Pharm Block 1 > 3 - Pharmacokinetics 2a > Flashcards

3 - Pharmacokinetics 2a Flashcards

1
Q

Absorption, distribution, and excretion of drugs all involve what?

A

The movement of drugs across cell membranes.

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2
Q

What types of molecules can diffuse readily through the membrane via passive diffusion?

A

Lipophilic compounds.

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3
Q

What is the rate of passive diffusion across a cell membrane determined by?

A

The partition coefficient of the drug into oil from water AND the concentration gradient across the membrane.

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4
Q

Most drugs are _____ acids or _____ bases and can exist in either _____ or _____ forms.

A

Weak acids or weak bases

and can exist in either charged or uncharged forms.

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5
Q

What version of a weak acid will likely passively diffuse through cell membranes?

A

HA, the protonated uncharged version.

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6
Q

Low pH means that an acid is most likely in what form? What happens as you increase the pH?

A

Protonated form.

As you increase the pH, the concentration of H ions will decrease and the weak acid will exist mostly in the A- form.

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7
Q

What is the pKa?

A

The pH at which there’s an equal amount of the protonated and unprotonated forms of an acid.

The negative log of the acid dissociation constant.

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8
Q

What is [HA]/[A-] determined by?

A

The pH of the environment and the pKa of the drug.

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9
Q

Write out the Henderson-Hasselback equation?

A

Log([protonated]/[unprotonated]) = pKa - pH

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10
Q

What form is a weak base in when it’s charged? What about when its uncharged?

A

Protonated when charged.

Unprotonated when uncharged.

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11
Q

When can weak acids or bases cross a membrane?

A

When they’re UNcharged.

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12
Q

What are the principles of ion trapping?

A

Acidic drugs accumulate on the side of the membrane that’s more BASIC (because A- can’t cross the membrane)

Basic drugs accumulate on the side of the membrane that’s more ACIDIC (because BH+ can’t cross the membrane).

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13
Q

Morphine, a weak base, can sometimes be detected in the stomach contents following an IV overdose. How can this happen?

A

Because weak bases accumulate on the side of the membrane that’s more acidic because BH+ can’t cross the membrane.

The stomach is more acidic than the plasma.

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14
Q

Describe the movement of passive diffusion.

A

Bidirectional

Driven by the concentration gradient.

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15
Q

What is carrier mediated transport?

A

Transport of a molecule across a barrier that’s mediated by binding of the solute to a protein transporter.

  • can move hydrophilic molecules
  • can move molecules against their gradient
  • provides specificity
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16
Q

What is facilitated diffusion?

A

Carrier mediated diffusion, but driven by the concentration gradient (ie no energy input is needed).

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17
Q

What is an example of facilitated diffusion?

A

Glucose transporters allow the movement of glucose into the cell; this is driven by the concentration gradient of glucose.

Allows for selectivity (ie can tell glucose from fructose).

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18
Q

What is the p-glycoprotien “ABC” pump? Where does the energy come from?

A

ATP binding cassette family of proteins.

Binds lipophillic drugs that have entered cells and mediates their efflux through the cell.

Energy from ATP hydrolysis.

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19
Q

What are ABC pumps encoded by?

A

The multidrug resistant gene; this means that they can be induced in response to exposure to various drugs

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20
Q

What are two types of secondary active transport?

A

Co-transport and anti-transport (exchangers).

Move two different solutes, one of which is against its concentration gradient coupled to the movement of the other down its conncentration gradient (usually Na or H).

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21
Q

What is bioavailability (F)? What is the bioavailability of an IV administered drug?

A

The fraction of the administered dose of drug that reaches the circulation.

IV administered drug would have an F=1.

22
Q

What is the first pass effect and enterohepatic cycling?

A

First pass: drug metabolized in the liver or excreted back into the intestines through biliary excretion during its “first pass” through liver.

Enterohepatic cycling: goes around in useless circle and doesn’t make it to total circulation.

Never reaches systemic circulation and therefore reduces the bioavailability considerably.

23
Q

What does it mean if the preparations of two drugs are bioequivalent?

A

They are the same drug, with the same route of administration, with the same amount of drug entering the circulation at the same RATE.

24
Q

Describe the route of orally administered drugs? What type of drugs are absorbed?

A

Absorbed from the GI tract mostly via passive diffusion (absorption) which favors absorption of unionized drugs.

Weak acids in the protonated form and weak bases in the unprotonated form absorbed.

25
Q

Why are most drugs not absorbed in the stomach? Where are they usually absorbed and how does this occur?

A

Stomach is very acidic (1-2), lined with thick mucous, and have a small SA.

Upper intestine have a very large SA and a pH ~7 where most drugs are absorbed even if the drug is ionized because equilibrium is not reached with the moving blood compartment which drives the absorption of the drug.

26
Q

Increased gastric emptying has what effect on drug absorption?

A

It increases the rate of drug absorption.

This is why some medications are recommended that you take with foo, because it can help control the absorption rate.

27
Q

What effects the rate of absorption of a drug other than gastric emptying times? How can this be taken advantage of for our benefit?

A

Dissolution of a solid drug.

How the drug is formulated, such as coating with hard-to-dissolve agents for slow or uniform dissolution (controlled release preparation).

Particle sizes.

28
Q

What are some drawbacks of controlled release preparations?

A

Greater variability among patients and toxicity if all the drug is released at once.

29
Q

What is the purpose of enteric coatings?

A

Protects the drug from stomach acid and the stomach from the drug.

Better taste.

Don’t want the coating completely impervious

30
Q

What are two other methods of giving drugs via the extended GI tract? What are the pros and cons of these methods?

A

Sublingual and buccal.

Blood drains into the SVC and avoids first pass in the liver.

Small surface area, so the drug needs to be lipophilic (ready to pass through membranes) and should be a small amount.

31
Q

What method of drug delivery may be useful is a patient cannot or will not swallow? What are the advantages and disadvantages?

A

Rectal.

50% less first pass than orally administered drugs,

Disadvantages: variable absorption, can be incomplete, irritating to the rectal mucosa, uncomfortable.

32
Q

What are the advantages and disadvantages to transdermal administration?

A

Epidermis is nearly impermeable barrier to non-lipophilic substances.

Permeable to lipophilic drugs. best when skin is hydrated and there’s an occlusive water tight dressing such as in patches.

33
Q

What are parenteral injection?

A

“without the intestine”

IV: no absorption needed
SubQ and intramuscular: depot of drug in either dermis or muscle and drug diffuses to nearby capillaries to enter the bloodstream.

34
Q

Parenterally administered drugs distribute where before the liver? What happens there?

A

The lungs, which have very similar metabolic enzymes as the liver that can transform the drug.

Filters particulates too large for the circulation and volatile agents can diffuse into the expired air.

Lipophilic agents can accumulate and redistribute.

35
Q

What are some benefits of IV injections/infusions? What are some disadvantages?

A

Good: Completely bioavailable (F=1), Immediate action, delivery highly controlled, dose and rate can be rapidly adjusted. Irritating agents are diluted by the entire blood volume.

Bad: route of no return, needs close monitoring, patent vein, and experienced staff.

36
Q

What are requirements for drugs to be administered subQ?

A

Drugs must be non-irritating, and not painful or damaging to tissues.

Can add vasoconstrictors to delay the absorption.

37
Q

What does the rate of absorption of lipophilic drugs depend on? How do large hydrophilic drugs enter circulation? What about proteins?

A

The drug solubility in interstitial fluid and the area of the capillary bed in the vicinity.

Large hydrophilic: pass through large aqueous channels in the capillaries.

Proteins: slowly via the lymphatic system.

38
Q

What is the purpose of delivering agents to the airway for pulmonary absorption?

A

Used to deliver volatile agents; very rapid.

Drugs to treat the airway.

39
Q

What type of drugs are best applied via mucous membranes? How does the eye absorb drugs?

A

Lipophilic drugs.

Eye requires absorption through cornea and can get into systemic via nasolacrimal dust. This can delay absorption and reduce systemic effects.

40
Q

What are three novel drug delivery methods that are being developed?

A

Drug eluting stents that are placed into vessels.

Targeting of drugs using antibodies.

Activation of drugs held in a polymer at the site of action.

41
Q

What does the extent and rate of drug delivery depend on?

A
  1. Blood flow: first phase is to highly perfused organs (most of the drug) and second phase is more poorly perfused organs and the equilibration it slow.
  2. Capillary permeability
  3. Drug binding to plasma proteins
42
Q

What effects capillary permeability of drugs?

A

Loose endothelial junctions allow paracellular movement of most drugs into tissues via hydrostatic pressure. (this is opposed by osmotic pressure pushing from interstitial fluid to the capillary.

Brain has tight junctions so this doesn’t occur.

43
Q

Why is there not much ion trapping between tissues and capillaries?

A

Because the pH values of blood and most tissues are the same.

44
Q

What plasma proteins can drugs bind to?

A

Albumin: negatively charged so acidic drugs bind

Alpha 1-acid glycoprotein: negatively charged so basic drugs bind.

45
Q

What equation describes the relationship between drugs and proteins in the blood?

A

[DP] = [total protein]*[drug]/(Kd +[drug])

For most drugs given repeatedly, [drug] is constant and so is [DP].

46
Q

What effect does drug protein binding have?

A
  1. Protein binding presents drug from leaving the dirculation
  2. Drug responses are a funciton of the FREE drug not protein bound
  3. At equilibrium, the amount of free drug is constant so protein binding doesn’t have a large effect
  4. Equil is perterbed transiently is plasma protein concentrations increase or is there’s changes in competitors for the binding sites.
47
Q

How can protein binding be affected by disease states? What are two examples?

A

Liver disease: reduced albumin means that you may need to decrease the dose because more of the drug will be free.

Immune activation: can increase alpha 1-acid glycoprotein and you may need to increase the dose of the drug.

48
Q

Where can drugs accumulate?

A

Lipophilic drugs can be stored for long periods in fat.
-THC

Drugs that bind divalent cations and heavy metals can accumulate in the bone and teeth.

49
Q

What is redistribution of drugs? What is redistribution a factor for?

A

Mechanism for termination of action of a drug due to it’s redistribution from the tissue or site of action to tissues in which it’s inactive.

Factor for highly lipid soluble drugs, drugs acting on high blood flow organs like brain or heart, and those administered by IV injection or inhalation.

50
Q

What allows certain drugs to get into the brain?

A

Unionized, not protein bound, highly lipophilic.

Or if the drugs are substrates for amino acids or sugar carrier (sneak in because they look like nutrients).

51
Q

What opposes drug entry into the brain?

A

Efflux mechanisms:
~ p-glycoprotein (ABC pumps): for lipophilic drugs, is inducible
~ organic anion transporting polypeptide (OATP) for negatively charged molecules

These export many drugs from CNS

52
Q

What are important factors for placental transfer of drugs?

A

Lipophilicity, unionized drug, protein binding.

Fetal plasma more acidic so it traps basic drugs.

Carrier present for essential nutrients and amino acids.

Pharm Block 1 (11 decks)

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