Pharmacokinetics - Sinal 2

Question 1

Pharmacokinetics

Answer 1

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

Question 2

Pharmacokinetic differences

Answer 2

Major determinant of patient response to drugs

Differences between how they absorb drugs, metabolize, receptors

Question 3

Routes for drug administration

Answer 3

1. Enteral
2. Parenteral
3. Topical

Question 4

Enteral drug administration

Answer 4

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

Question 5

First pass effect

Answer 5

Drug metabolism by intestine and liver enzymes

Reduces amount of drug that ultimately reaches the systemic circulation: reduces bioavailability

Question 6

Parenteral

Answer 6

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

Question 7

Injection

Answer 7

Rapid delivery

100% bioavailability

Question 8

Topical

Answer 8

Local effect

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

Question 9

Physical factors that affect oral drug absorption

Answer 9

Concentration differences across membrane, size, polarity, ionization

Question 10

Passive drug absorption of the small intestine

Answer 10

Majority of drug absorption

Large surface area, brush border, extremely high bloodflow

Question 11

Physiological factors that affect oral drug absorption

Answer 11

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

Question 12

Drug distribution

Answer 12

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

Question 13

Vd

Answer 13

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

Question 14

Small Vd

Answer 14

Infers retention within the plasma volume

Question 15

Large Vd

Answer 15

Infers retention in volumes outside of plasma

Question 16

Factors causing high Vd

Answer 16

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

Question 17

Factors causing low Vd

Answer 17

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

Question 18

Albumin

Answer 18

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)

Question 19

Elimination

Answer 19

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

Question 20

Drug metabolism

Answer 20

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

Question 21

Phase 1 metabolism

Answer 21

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

Question 22

Phase 2 metabolism

Answer 22

Addition of large polar groups to small, reactive functional groups

Question 23

Cytochrome P450

Answer 23

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

Question 24

Inhibitors of CYP3A4

Answer 24

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

Question 25

Inducers of CYP3A4

Answer 25

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

Question 26

CYP3A4

Answer 26

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

Question 27

Felodipine and CYP3A4

Answer 27

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

Question 28

Terfenadine and CYP3A4

Answer 28

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

Question 29

Cyclosporine and Rifampicin

Answer 29

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

Question 30

Inter individual differences in drug metabolism

Answer 30

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

Question 31

CYP2D6

Answer 31

Metabolizes ~15% of drugs
Highly polymorphic
4 genotypic groups:
1. Poor metabolizers
2. Intermediate metabolizers
3. Extensive metabolizers (most common in all ethnic groups)
4. Ultrarapid metabolizers (increased risk of respiratory depression)

Question 32

Kidney drug excretion

Answer 32

Most important route for parent drug and metabolites
Excretion in urine
Promoted by drug metabolism
Organic cation transporters and organic anion transporters
Most polar and ionized compounds are not reabsorbed efficiency by passive diffusion and are excreted in urine

Question 33

Liver drug excretion

Answer 33

Important for a number of drugs
Excretion in bile
Promoted by drug metabolism

Question 34

Organic cation transporters

Answer 34

OCT, MATEs (multidrug and toxin extrusion proteins) and Pgp (P-glycoproteins)
In kidney proximal tubules

Question 35

Organic anion transporters

Answer 35

OATs, MRPs (multidrug resistance proteins)

Question 36

Initial drug concentration

Answer 36

Co= Q/Vd

Question 37

Plasma concentration

Answer 37

C=Co e^(-kel t)

Question 38

Kel

Answer 38

Elimination rate constant

Question 39

Half-life

Answer 39

t1/2= 0.693/kel

Question 40

Clearance

Answer 40

Volume of plasma from which drug is removed per unit of time
Reflects elimination of drug through metabolism and various routes of excretion
Cl=rate of elimination/C
Cl=kelQ/Co
Cl=kel Vd
Cl= 0.693Vd/(t1/2)

Question 41

Continuous IV infusion

Answer 41

To maintain drug levels in blood
Plasma concentration will rise fast at first, then more slowly and reach a plateau where rate of administration = rate of elimination = Css

Question 42

Css

Answer 42

Steady state blood concentration
If time to achieve Css is too long, an initial higher dose is used with subsequent doses being smaller maintenance doses
Usually takes 3 half-lives

Question 43

Multiple doses

Answer 43

Can be used to achieve steady state

Steady state blood concentration that oscillates between Cmax and Cmin

Question 44

Target concentration strategy

Answer 44

Assumes that for most drugs, magnitude of therapeutic effect and risk for adverse reactions is predictable given target concentration in the blood
Dose required to achieve TC will vary between individuals
Pharmacokinetic models and parameters can be used to reliably predict the dose required to achieve TC and therapeutic benefit