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Flashcards in Pharmacokinetics - Sinal 2 Deck (44)
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1

Pharmacokinetics

Quantitative study and characterization of the time course of drug concentrations in the body
Can predict concentration of drug in blood and magnitude of effect hours later, absorption, distribution and elimination
Utilizes simplified mathematical representations to model physiological processes

2

Pharmacokinetic differences

Major determinant of patient response to drugs
Differences between how they absorb drugs, metabolize, receptors

3

Routes for drug administration

1. Enteral
2. Parenteral
3. Topical

4

Enteral drug administration

Desired effect is systemic (given via digestive tract)
Oral is most common and convenient route (but subject to first pass effect)
Not suitable for drugs that are rapidly metabolized, acid labile or known to cause GI irrigation
Gastric feeding tube or rectal

5

First pass effect

Drug metabolism by intestine and liver enzymes
Reduces amount of drug that ultimately reaches the systemic circulation: reduces bioavailability

6

Parenteral

Desired drug effect is systemic
Route other than digestive tract
Injection, transdermal, transmucousal

7

Injection

Rapid delivery
100% bioavailability

8

Topical

Local effect
Epicutaneous, inhalation, eye drops, ear drops, intranasal, vaginal

9

Physical factors that affect oral drug absorption

Concentration differences across membrane, size, polarity, ionization

10

Passive drug absorption of the small intestine

Majority of drug absorption
Large surface area, brush border, extremely high bloodflow

11

Physiological factors that affect oral drug absorption

1. Gastrointestinal motility
2. Metabolism
3. Changes in pH of gastrointestinal tract (affects ionization)

12

Drug distribution

Process in which a drug reversibly leaves the blood and is distributed throughout the tissues of the body
Extent is dependent on blood flow, ability of drug to transverse cell membranes, and degree of binding to blood proteins
Distribution of a drug to target organ is critical requirement for achieving therapeutic benefit

13

Vd

Volume of distribution= total amount of drug in body/initial plasma concentration
Apparent volume of fluid which an administered drug is dispersed in
Assumes equal partitioning throughout the body
Determined from measurement of initial plasma drug level after IV bolus injection

14

Small Vd

Infers retention within the plasma volume

15

Large Vd

Infers retention in volumes outside of plasma

16

Factors causing high Vd

1. High lipophilicity
2. Low polarity
3. Low ionization
4. Low molecular weight
*Increased ability to traverse biological membranes of cells

17

Factors causing low Vd

1. Low lipophilicity
2. High polarity
3. High ionization
4. High molecular weight
5. Binding to blood proteins, ie. Albumin

18

Albumin

Binds many drugs
Bound drug is therapeutically inactive
Binding is reversible, but can cause potentially dangerous increase in blood concentration of free drug (great concern for high bound >90% drugs with narrow therapeutic window)

19

Elimination

Major: urine, bile
Minor: saliva, sweat, milk, other body fluids, exhalation

20

Drug metabolism

Biotransformation
Metabolism increases polarity, ionization and water solubility
Metabolites often are deactivated, prodrugs have more active or toxic metabolites
Liver is major site of metabolism of drugs
Lipophilic drugs are poorly excreted by the kidney and the liver

21

Phase 1 metabolism

Creation or unmasking of small polar or reactive functional groups
Usually rate limiting

22

Phase 2 metabolism

Addition of large polar groups to small, reactive functional groups

23

Cytochrome P450

Most important contributor to metabolism of most drugs
Extremely broad substrate range
Expression levels very among individuals
Enzymatic activity can be inhibited by drugs and diet components: decreases rate of metabolism of co-administered drugs
Expression levels can be induced by drugs and diet components

24

Inhibitors of CYP3A4

Antifungals (ketoconazole), antibiotics (erythromycin), diet (grapefruit juice)

25

Inducers of CYP3A4

Anticonvulsants (phenobarbital), steroids (dexamethasone), HIV protease inhibitors (saquinavir), antibiotics (rifampicin)

26

CYP3A4

Most relevant enzyme to human drug metabolism: must abundant CYP in intestine and liver, very broad substrate specificity, metabolizes 50-70% of drugs

27

Felodipine and CYP3A4

CYP3A4 makes felodipine an inactive metabolite M3
Dihyropyridine calcium channel antagonist (relaxes smooth muscle) for treatment of hypertension
Poor bioavailability: extensive first-pass metabolism
Coadministration with CYP3A4 inhibitors/substrates causes plasma concentration of felodipine to increase and cause excessive hypotension, cardiac side effects

28

Terfenadine and CYP3A4

Terfenadine is metabolized by CYP3A4 to active Fexofenadine
Terfenadine is toxic: inhibition of K channel, life-threatening cardiac arrhythmias
CYP3A4 inhibitors increase likelihood of cardiac toxicity
Withdrawn from market

29

Cyclosporine and Rifampicin

Rifampicin induces expression of CYP3A4
Co-administration of the two reduces plasma levels of cyclosporine and can cause acute rejection episodes
Increases cyclosporine dose requirement by 3-fold

30

Inter individual differences in drug metabolism

1. Diet, environment
2. Age
3. Disease
4. Genetic factors