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Pharmacology > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Draw the flow chart outlining the relationship between pharmacokinetics and pharmacodynamics.

A

Pharmacokinetics

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2
Q

Routes for drug administration

A
  • systemic (parenteral and enteral)

- local (topical)

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3
Q

Enteral drug administration

A
  • substance given via the digestive tract
  • oral is most common and convenient route
  • others are gastric feeding tube, rectal
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4
Q

First pass effect

A
  • metabolism by intestine and liver enzymes

- reduces amount of drug that ultimately reaches the systemic circulation (bioavailability)

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5
Q

Oral administration is not suitable for drugs that are…

A
  1. rapidly metabolized
  2. acid labile- would be broken down in high acidity of the stomach
  3. known to cause GI tract irritation
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6
Q

Parenteral drug administration

A
  • drug is given by route other than digestive tract
  • injection
  • transdermal (nicotine patches)
  • transmucosal (buccal, insufflation, inhalational)
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7
Q

Drug administration by injection

A
  • intravenous, intramuscular, subcutaneous
  • intravenous gives 100% bioavailability
  • bypasses first pass effect
  • suitable for acid labile drugs
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8
Q

Cons of drug administration by injection (3)

A
  • may require professional admin
  • costs assoc w/ injection materials and disposal
  • requires sterile prep
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9
Q

Topical drug administration

A
  • local effect

- substance is applied directly where its action is desired

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10
Q

Oral Drug Absorption

A
  • the process by which a drug moves from the site of admin (GI tract) to the site of measurement (blood)
  • requires passage across membranes of cells (enterocytes) that comprise the intestine wall
  • mostly occurs by passive diffusion across membranes
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11
Q

Physiochemical Factors that affect oral drug absorption (4) and explain.

A
  1. concentration difference across membrane
  2. size
  3. polarity
  4. ionization
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12
Q

Why does the majority of absorption for most drugs occur in the small intestine?

A
  1. extremely large SA
    - 250m2
    - 1000x > stomach
    - villi, microvilli
  2. extremely high blood flow
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13
Q

Physiological factors that affect oral drug absorption (3)? Explain

A
  1. gastrointestinal motility
  2. metabolism
  3. changes in pH of GI tract
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14
Q

Drug Distribution

A

Process by which a drug reversibly leaves the blood and is distributed throughout the tissues of the body
-distribution to target organ is critical for achieving therapeutic benefit

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15
Q

The extent of drug distribution is dependent upon what factors? (4)

A
  1. blood flow
  2. ability of drug to traverse cell membranes
  3. degree of binding to blood proteins (albumin)
  4. unique properties of drug/tissue
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16
Q

Volume of distribution (Vd)

A

The apparent volume of fluid into which an administered drug is dispersed

  • determined from measurement of initial plasma drug level after IV bolus injection
  • apparent b/c assumes that the conc measured in the plasma accurately reflects the conc in the interstitial and intracell vol => every drug should have a Vd of 42L
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17
Q

A small Vd infers?

A large Vd infers?

A

small=retention in the plasma

large=retention in volumes outside of plasma

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18
Q

As Vd increases, dose required to achieve a particular initial plasma conc ?

A

Increases

19
Q

What are 2 factors that contribute to high Vd?

A
  1. physiochemical properties of drug

2. physiological properties of tissues

20
Q

What physiochemical properties of drug favour a high Vd?

A

-high lipophilicity
-low polarity
-low ionization
-low molecular weight
=>increased ability to traverse biological membranes of cells

21
Q

What are 2 factors that contribute to low Vd?

A
  1. physiochemical properties of drug

2. binding to blood proteins (blood serum albumin)-explain

22
Q

? and ? are the major determinants of a drugs duration in the body

A

-metabolism and excretion

23
Q

The goal of metabolism is to increase ?, ? and ? of drugs.

A
  • polarity
  • ionization
  • solubility
24
Q

Bioavailability

A

The amount of administered drug that reaches the systemic circulation in unchanged form following administration by any route

25
Q

Phase I Metabolism

A

Creation or unmasking of small polar or reactive functional groups
-usually rate limiting step
eg hydroxylation

26
Q

Phase II Metabolism

A

Addition (conjugation) of large polar groups to small reactive functional groups
eg glucuronidation

27
Q

The cytochrome P450 gene superfamily

A
  • 57 individual genes

- families 1, 2, 3 are most relevant to drug metabolism -Phase I

28
Q

T or F: CYP3A4 has very broad substrate specificity

A

True

29
Q

What are 3 inhibitors of CYP3A4?

A
  1. antifungals (ketoconazole)
  2. antibiotics (erythromycin)
  3. diet (grapefruit juice)
30
Q

What are 4 inducers of CYP3A4?

A
  1. Anticonvuslants (phenobarbital)
  2. Steroids(dexamethasone)
  3. HIV protease inhibitors (saquinavir)
  4. Antibiotics (rifampicin)
31
Q

CYP3A4 is most abundant in ? and ?

A

intestine and liver

32
Q

Explain the interaction of felodipine with CYP3A4

A
  • dihydropyridine Ca channel antagonist for the treatment of hypertension
  • poor oral bioavailability b/c deactivated by CYP3A4
  • coadministration w/ grapefruit juice or other CYP3A4 substrates/inhibitors increase bioavailability and plasma conc up to 5 fold, increases risk for hypotension and cardiac side effects (HR increase)
33
Q

Explain the interaction of Terfenadine (marketed as seldane) with CYP3A4.

A
  • non sedating antihistamine
  • prodrug
  • extensively metabolized by CYP3A4 to fexofenadine (allegra)
  • serious cardiac side effects at high concentrations of terfenadine (inhibition of K channels, life threatening arrhythmias)
  • CYP3A4 inhibitors increase likelihood of cardiac toxicity
  • withdrawn from market in Canada in 1999
34
Q

CYP3A5 Induction caused by cyclosporine and rifampicin

A

cyclosporine-immunosupressant drug used to prevent rejection of transplanted organs
-metabolized to inactive metabolite by CYP3A4
Rifampicin
-antibiotic used to treat a variety of bacterial infections
-induces expression of CYP3A4
Coadministration of cyclosporin and rifampicin
-reduces plasma levels of cyclosporin
-can result in acute rejection episodes
-increases dose requirement by 3 fold

35
Q

What are 4 inter individual differences in drug metabolism?

A
  1. Diet and environment (smoking, occupational exposure)
  2. age (children exhibit differences from adults, drug metabolism reduced in elderly)
  3. disease (drug metabolism reduced with disease)
  4. genetic factors (polymorphisms in genes, affects expression level, inherent enzyme activity and response to inducers)
36
Q

Cytochrome P450 2D6

A
  • metabolizes 15% of drugs

- highly polymorphic

37
Q

What are 4 CYP2D6 phenotypic groups?

A
  1. poor metabolizers (caucasians)
  2. intermediate metabolizers (east asia and subsaharan africa)
  3. extensive metabolizers (normal, most common phenotype)
  4. Ultrarapid metabolizers (elevated expression and activity, Middle east, north africa, oceania)
38
Q

Codeine

A
  • narcotic analgesic prescribed after surgery
  • often combined w/ acetaminophen
  • analgesic effect is due to morphine metabolites generated by CYP2D6 metabolism
39
Q

How do CYP2D6 polymorphisms affect codeine analgesia?

A

Poor metabolizers may experience reduced analgesia (pain relief) from a normal dose of codeine due to reduced levels of morphine metabolites
- Mistaken for drug-seeking behaviour?
Ultrarapid metabolizers may experience adverse effects (e.g. respiratory depression) as a consequence of a rapid accumulation of morphine metabolites

40
Q

What is the role of the kidney in drug excretion?

A
  • Quantitatively, most important route for parent drug and metabolites
  • Excretion in urine
  • Promoted by drug metabolism
41
Q

What is the role of the liver in drug excretion?

A
  • excretion in bile

- Promoted by drug metabolism

42
Q

What are other structures impt for drug excretion (other than liver and kidney)

A
  • sweat, tears, repro fluids, milk, lung

- may be influenced by drug metabolism

43
Q

How does metabolism promote renal drug excretion

A

-by producing metabolites with greater polarity, ionizability and reduced lipophilicity (organic anions and cations)

44
Q

What are the 2 major classes of transport proteins involved in renal drug secretion?

A
  • Organic cation transporters (OCTs, MATEs, P-gp)
  • organic anion transporters (OATs, MRPs)
  • present on faces of nephron tubule epithelial cells, most abundant is proximal tubule

Pharmacology (9 decks)

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