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Pharmacology > Pharmacokinetics: Physiology of Drug ADME > Flashcards

Pharmacokinetics: Physiology of Drug ADME Flashcards

1
Q

How do drugs cross biological membranes?

A
  • passive diffusion
  • filtration (pore)
  • active transport
  • endocytosis
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2
Q

What factors affect passage of drugs across a biological membrane (distribution of drugs around the body)?

A
  • perfusion (blood flow)
  • drug’s lipid solubility
    • ionization (more ionized, less likely to pass thru membrane)
  • binding of drug w/ plasma membrane and/or tissue proteins (determines how much “free drug” is available)
  • transporters (transport drugs/metabolites out of cells)
  • protected body compartments (blood brain barrier, etc.)
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3
Q

Identify the major metabolic pathways by which drugs are chemically modified.

A
  • Phase I or Non-synthetic (drug is split)
  • Phase II or Synthetic (something is added to the drug to make it more hydrophilic via conjugation)
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4
Q

Define the Phase I metabolic reaction.

A

Phase I metabolic reactions: HOR - Hydrolysis, Oxidation, ReductionEnzymes add or unmask a polar moiety in the drug to make it more soluble via oxidation/reduction reactions.

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5
Q

Define the Phase II metabolic reaction.

A

Phase II metabolic reactions: *GAS* = Glucuronidation, Acetylation, Sulfation

  • Conjugation with a polar or charged group
  • require a donor molecule as source of conjugated group
  • High capacity reactions (not rate limiting)
  • Usually follow a non-synthetic (Phase I) reaction
  • Facilitate excretion and usually inactivate
  • Biological function
  • Major conjugation reactions:
    • Glucuronidation (the major conjugation reaction)
    • Sulfation
    • Acetylation
    • Glutathione conjugation
    • Glycine conjugation
    • Methylation
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6
Q

Name the major cytochrome P450 substrates for CYP1A2:

A

Substrates: Acetaminophen (important because of toxicity factor), Caffeine, Theophylline, Warfarin

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7
Q

Name the major cytochrome P450 substrates for CYP2A6:

A

Substrates: Warfarin (minor), Zidovudine

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8
Q

Name the major cytochrome P450 substrates for CYP2C9:

A

Substrates: Hexobarbital, Ibuprofen, Phenytoin, Tolbutamide, Trimethadione, **S-Warfarin (CYP2C9 is the main enzyme that metabolizes the biologically active form of warafin)

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9
Q

Name the major cytochrome P450 substrates for CYP2C19:

A

Substrates: Diazepam, Omeprazole, Propanolol

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10
Q

Name the major cytochrome P450 substrates for CYP2D6

A

Substrates: Amitriptyline, Codeine (converts to morphine), Fluoxetine, Hydrocodone, Timolol

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11
Q

Name the major cytochrome P450 substrates for CYP2E1

A

Substrates: Acetaminophen, Ethanol, Ethanol

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12
Q

Name the major cytochrome P450 substrates for CYP3A4

A

*the really important one*

Substrates:

  • steroids (testosterone, progesterone, cortisol, etc.)
  • calcium channel blockers (nifedipine, diltiazem, verapamil)
  • benzodiazepines (diazepam, triazolam)
  • amiodarone
  • **erythromycin (and other macrolide antibiotics)
    • Can lead to toxicity if administered when CYP3A4 is blocked
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13
Q

Explain the critical steps in the P450 reaction pathway, including the roles of NADPH, cytochrome P450 reductase and molecular oxygen.

A

Net reaction is oxidation R-H -> R-OH

Requires:

  • NADPH important Cofactor - used 2x
  • molecular Oxygen
  • Cytochrome P450 reductase
  1. Drug substrate (R-H) combines with oxidized (Fe3+) cytochrome P450 to form a binary complex.
  2. NADPH donates an electron to the flavoprotein, NADPH cytochrome P450 reductase, which in turn reduces the oxidized CYP450-drug complex.
  3. The same flavone reductase introduces a second electron (also from NADPH) to reduce molecular oxygen and form an “activated oxygen” - CYP450-drug complex.
  4. This complex transfers oxygen to the drug substrate to form the oxidized drug product (R-OH), liberates water, and leaves free oxidized (Fe3+) CYP450 to react with another drug molecule.
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14
Q

Identify other non-P450 Phase I reactions.

A
  • Oxidation–Flavin monooxygenases, alcohol dehydrogenase, amine oxidases
  • Hydrolysis–Particularly esterases and amidases
  • Reduction–Nitro- and Azo- compound reduction by reductases
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15
Q

List the major conjugation reactions (Phase II).

A
  • Glucuronidation (the major conjugation reaction)
  • Sulfation
  • Acetylation
  • Glutathione conjugation
  • Glycine conjugation
  • Methylation
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16
Q

Explain mechanisms that result in increased (enzyme induction) rates of drug metabolism.

A
  • ligand (substrate of metabolism enzyme) binds nuclear receptors which activate transcription of metabolic enzymes (CYP450 -> metabolize drugs; Conjugating enzymes; drug transporters)
  • the metabolic enzyme then acts on the ligand or potentially other drugs in the body.
  • effect is increased metabolism of drugs:
    • increased toxicity from metabolites
    • ineffective treatments due to drug being metabolized too fast
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17
Q

What ligands activate the aryl hydrocarbon nuclear receptor (AHR) and pregnane X nuclear receptor (PXR) during drug metabolism enzyme induction?

A
  • AHR: omeprazole, target genes: CYP1A1, CYP1A2
  • PXR: rifampin, target genes: CYP3A4, MDR1
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18
Q

How does chronic alcoholism affect acetaminophen metabolism?

A
  • alcohol abuse leads to CYP2E1 overproduction
  • a lot of CYP2E1 can metabolize acetaminophen into NAPQI, a toxic product
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19
Q

Explain mechanisms that result in decreased (enzyme inhibition) rates of drug metabolism.

A
  • inhibitor covalently interacts with enzyme heme iron
    • ex. erethromycin covalently binds to the heme group of P450 enzymes => inactivation
    • ex. triazole antifungals
    • ex. ritonavir (ART)
  • inhibitor alkylates and inactivate heme protein
    • ex. chloramphenicol
  • inhibitor competes for P450 with other substrates, and/or availability of NADPH may become rate-limiting
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20
Q

What are the nutritional factors that may influence drug metabolism in humans.

A

Nutrition:

  • Grapefruit and grapefruit juice: a component of the juice binds to and inactivates CYP3A4
  • Isosafrole, safrole: CYP1A1, CYP1A2 inhibitor - found in root beer and perfume.
  • Ethanol: CYP2E1 inducer (note importance in acetaminophen metabolism)
  • Charcoal broiling: CYP1A enzyme induction
  • Tobacco (not really a food): CYP1A induction (benzo[a]pyrene)
  • Cruciferous vegetables (like broccoli): CYP1A induction
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21
Q

Describe the mechanism of some common drug-drug interactions.

A
  • Alteration in elimination - reducing ability for an organ to clear a drug leads to increased drug in body
  • Physico-chemical interactions (divalent cations like Ca2+ and fluroquinolones)
  • Additive/synergistic functional interactions - the stacking effects of drugs
    • stacking antibiotics -> increase thearpy
    • stacking antidepresents (EtOH & benzos) -> increase toxisity
    • stacking blood thinners (warfarin & NSAIDs or aspirin) -> increase bleeding
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22
Q

What are the four basic mechanisms of drug passage across membranes?

A

Passive diffusion, Filtration, Active transport and Endocytosis

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23
Q

What law governs passive diffusion?

A

Fick’s Law. Diffusion down a concentration gradient.

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24
Q

What determines molecular passage in the filtration method of drug passage across biological membranes?

A

The pore size. Molecules move down a concentration gradient.

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25
Q

What feature distinguishes Active transport most prominently against the other methods of drug transport across membranes?

A

It requires ATP and can go (and often does) against the concentration gradient.

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26
Q

MDR1 is aka?

A

Multi Drug Resistance gene 1 and it makes P-glycoprotein. Which is an ABC drug transporter, important for anti-tumor drugs.

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27
Q

Endocytosis is…?

A

The entrance of extracellular substances into the cell by binding a receptor on the cell surface and being pulled into the cell within an individual lipid membrane derived from the cell surface. (Potential vector for virus entrance into cells).

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28
Q

What are 3 key factors that influence diffusional drug passage across the cellular membrane?

A

Concentration gradient, Lipid Solubility and Ionization

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29
Q

How does concentration gradient affect the diffusional drug passage across the cellular membrane?

A

Drugs that are able to pass through the membrane will move from an area of lower concentration to an area of higher concentration.

30
Q

How does lipid solubility affect the diffusional drug passage across the cellular membrane?

A

The chemical structure of a drug determines the solubility. If it is lipid soluble the drug will pass more easily through the membrane.

31
Q

How do we measure the lipid solubility of a drug?

A

With the “Lipid solubility coefficient” - A higher coefficient means that the molecule is more easily able to pass through the lipid membrane.

32
Q

Two barbituate drugs have lipid solubility coefficients of 3.3 - (thiopental) and 0.002 - (barbital), which passes more easily through lipid membranes?

A

Thiopental. (Which is why it is used to induce anesthesia, it acts faster because of its higher lipid solubility coefficient).

33
Q

How does drug ionization affect the ability to diffuse into cells?

A

Molecules which are charged will have a harder time passing through lipid membranes. Those which are uncharged are free from hydration shells and can often diffuse through the membrane. Hydration shells forming around charged ions block this passage.

34
Q

If a weak acid (pKa ~ 3.5) is put in an acidic environment (like the stomach pH 1.5) What do can you say about its ionization state and diffusion potential?

A

It will NOT be ionized and so will be able to diffuse into the stomach.

35
Q

What are the two drug transporter families we learned in lecture?

A
  • ABC (ATP Binding Cassette)
    • primary active transporter
    • uses ATP to drive drug transporter
  • ** SLC** (Solute Linked Carrier) super families
    • secondary active transporter
    • uses paired solute concetration gradient to drive drug transporter
    • symport (drug going in) and antiport (drug going out)
36
Q

Name an important example of the ABC super family and describe its mechanism.

A

MDR1 - Makes P-glycoprotein, an ABC that pumps solutes across cell membranes. (In the brain it often pumps drugs out by ATP hydrolysis, in other organs it can pump in or out depending on what it is used for).

37
Q

What are two examples of SLC transporters and what do they transport?

A
  • SERT - The serotonin transporter. (On which Prozac acts)
  • DAT - The Dopamine transporter. (On which cocaine and methylphenidate (Ritalin) act).
38
Q

How do facilitative transporters work?

A

They use ion coupled secondary active transport to move solutes across the membrane.

39
Q

What are the four routes of enteral drug administration?

A

Buccal cavity, stomach, small intestine and rectum.

40
Q

What are the five routes of parenteral drug administration?

A

Intravenous (IV), inhalation, intramuscular (IM), subcutaneous (SC) and percutaneous.

41
Q

What is the advantage of buccal cavity (sublingual) drug administration?

A

The drug enters the systemic circulation first by being absorbed under the tongue (instead of in the stomach or intestines) which avoids the first pass metabolism of the liver.

42
Q

What are the advantages/disadvantages of stomach absorption of a drug?

A

The low pH affects drug stability. Can easily absorb acidic (and weak base) drugs that are not ionized. Drugs are subject to first pass metabolism to the liver and then to the systemic circulation. Food slows absorption and reduces irritaiton.

43
Q

What are the advantages/disadvantages of intestinal absorption of drugs?

A

The pH of the intestines is around 6-7.4. Ease of absorption of most drugs. Subject to first pass metabolism.

44
Q

What are some advantages/disadvantages of rectal administration of drugs?

A

There is less irritation than the oral route. You may be able to avoid first pass metabolism depending on location within the rectum. This administration location is less well tolerated than the oral route.

45
Q

What are some advantages/disadvantages of intravenous drug administration?

A

Sends the drug directly into the drug stream. 100% absorption and no first pass metabolism.

46
Q

What are some advantages/disadvantages of drug administration by inhalation?

A

Requires the drug be volatile or gaseous drug, provides rapid absorption for anesthetics or asthma medications.

47
Q

What are some advantages/disadvantages of intramuscular drug administration?

A

Enters systemic circulation without first pass metabolism.

48
Q

What are some advantages/disadvantages of subcutaneous drug administration?

A

Slower absorption depending on blood flow?

49
Q

What are some advantages/disadvantages of percutaneous drug administration?

A

(Example steroid patches) useful for highly potent lipid soluble drugs.

50
Q

How can you describe the equilibrium between plasma bound drug in the body and free drug?

A

([Free drug]/[Kd][Free drug])

51
Q

Plasma protein binding - [total drug] = ?

A

[Free drug] + [Bound drug]

52
Q

How might lipophilic drugs interact with albumin?

A

They may become bound to it.

53
Q

(Mass of the Drug absorbed)/(plasma volume) = ?

A

Volume of Distribution

54
Q

Low volume of distribution indicates?

A

High plasma concentration

55
Q

High volume of distribution indicates?

A

Concentration of the drug in extravascular areas.

56
Q

Remember that bioavailability affects the amount of drug absorbed.

A

Also remember the implications for that in IV vs. Oral administration of the drug.

57
Q

Tissue accumulation of a drug can occur where in the body?

A

Really anywhere, but key locations are kidney, eye, lung, bone, and fat.

58
Q

What is the cause of drug accumulation in different organs?

A

It is caused by binding proteins unique to that organ or just accumulation of lipid soluble drugs in fat deposits.

59
Q

What happens to resevoirs of drugs (stored in organs) as blood concentration goes down?

A

The equilibrium will cause the drug to be released into the blood stream.

60
Q

Three factors affect the ability of drugs to enter the CNS, what are they?

A

There are relatively few pores in the blood brain barrier to allow entry, highly lipophilic drugs have a better chance of entry, ABC transporters (like MDR-1) pump many drugs that are able to enter, back out.

61
Q

Three special notes should be made of MDR-1 when it comes to CNS involvement.

A

Some drugs are especially good substrates for MDR-1 which means they should stay out of the CNS almost entirely. 1) Morphine which only has 10% of the CNS concentration compared to plasma concentration. (This is still enough for a therapeutic effect). 2) HIV proteases are pumped out quickly making the brain a safe haven for HIV3) Some anti-cancer drugs are pumped out quickly, making using them to treat brain cancers difficult.

62
Q

What 5 factors influence placental passage of drugs to a growing conceptus?

A

1) Lipid solubility2) Size and pH3) Placental Transporters4) Protein Binding5) Placental metabolism of drugs

63
Q

How is placental passage of drugs affected by Lipid Solubility?

A

More soluble drugs are able to pass more easily and enter the fetal circulation.

64
Q

How is placental passage of drugs affected by size and pH of the drug?

A

Most smaller drugs (250-500) can pass easily depending on their charge and lipophilicity. (500-1000MW) drugs have a harder time and large polar drugs can’t pass through it at all (like Heparin).

65
Q

What should be remembered about fetal blood circulation of drugs? (Specifically blood pH related)

A

Fetal blood has a pH of about 7.3 making slightly basic drugs more ionized preventing them from leaving fetal circulation and therefore accumulating.

66
Q

How is placental passage of drugs affected by placental transporters?

A

P-glycoprotein transporter (MDR-1 gene’s product) will affect certain drugs the same way they do for the brain. Namely that they pump them out. This has implications for HIV treatment because the viral protease inhibitors won’t be able to remain in fetal circulation and the child will have an increased risk of catching parental HIV.

67
Q

How is placental passage of drugs affected by protein binding?

A

Greater protein binding (via albumin usually) leads to lower levels of fetal circulation but may not affect very lipophilic compounds.

68
Q

How is placental passage of drugs affected by the placental metabolism of drugs?

A

The placental barrier acts as a block and sometimes a site of metabolism for drugs that are trying to enter fetal circulation. This can have the effect of either increasing or decreasing drug toxicity.

69
Q

List 4 of the main methods of drug elimination.

A

Renal clearance, Fecal clearance, Expired clearance (breathing them out), Breast milk clearance (usually very small concentrations).

70
Q

How does ionization affect the renal clearance of a drug?

A

Urine pH is about 5.5, and plasma pH is about 7.5. That means that weak bases tend to move from the plasma to the urine in the kidney. (And acids will do the reverse).

71
Q

How is drug dosing affected in children and the elderly?

A

Dosing should be adjusted for children using the manufacturers specifications (usually based on age, weight, and surface area of the skin (if the drug is administered topically). For the elderly you should expect potentially decreased renal clearance and/or reduced respiratory capacity.

72
Q

What are some drug classes known to cause clinically relevant interactions?

A
  • Anti-epileptics (low therapeutic index, CYP metabolism)
  • Protease inhibitors (co-administration with CYP inducers, example: rifampin)
  • Statins (metabolized by CYP3A enzymes in gut and liver)
  • Warfarin (metabolized by CYPs; highly protein bound)
  • Digoxin (multiple interactions, low therapeutic index)

Pharmacology (5 decks)

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