Pharmacokinetics

Question 1

Barriers for oral drug to the CNS

Answer 1

The wall of the intestine
The walls of capillaries that perfuse the gut
The blood-brain barrier

Question 2

Mechanisms of drug permeation

Answer 2

Aqueous diffusion = paracellular pathway
Lipid diffusion = transcellular pathway
Special carriers
Endocytosis and exocytosis = transcytosis

Question 3

Absorption

Answer 3

Transfer of a drug fro its site of administration to the bloodstream

IV delivery: complete absorption
Other routes: partial absorption

Question 4

First-pass effect

Answer 4

Oral drug is first metabolized in the gut wall and the liver before reaching systemic circulation

Question 5

Enteral routes

Answer 5

Oral
Sublingual: bypass first-pass effect
Rectal: partial avoidance of the first-pass effect

Question 6

Parenteral routes 4

Answer 6

Intravenous
Intramuscular
Subcutaneous
Intradermal

Question 7

Other routes 4

Answer 7

Oral inhalation
Nasal inhalation
Topical
Transdermal

Question 8

Factors that influence drug absorption

Answer 8

PH: uncharged is liposoluble
Surface area: largest in intestine
Blood flow: greater in intestine
Contact time
P=glycoprotein

Question 9

Henderson-Hasselbalch equation

Answer 9

pH -pKa = log(unprotonated form/protonated form)

Question 10

Ion trapping

Answer 10

Drug excretion by the kidney
Accelerate excretion by preventing reabsorption
Adjust urine pH to ionize the drug

Weak acids in alkaline urine
Weak bases in acidic urine

Question 11

P-glycoprotein

Answer 11

MDR1
Use ATP
Pump drugs out into the lumen, reduce drug absorption

Question 12

Bioavailability

Answer 12

F = AUC oral/AUC IV
AUC IV = 100%

Fraction of administered dose of a drug that reaches the systemic circulation
Plot plasma cocentrations of the drug vs. time
Area under the curve = AUC > extent of absorption

Question 13

Determinants for drug distribution 4

Answer 13

Blood flow
Drug binding to plasma and tissue proteins
Capillary permeability
Drug hydrophobicity

Question 14

Drug distribution to organs

Answer 14

First: liver, kidney, brain, and other well-perfused organs
Slower: muscle, most viscera, skin, fat

Question 15

Blood-brain barrier

Answer 15

Transcellular > highly soluble or have an active transporter

Endothelial cells of the brain capillaries have continuous tight junctions
Astrocyte endfeet surround the outside of capillary endothelial cells
P-glycoprotein actively transport drugs back into the systemic circulation

Question 16

Drug elimination

Answer 16

Metabolism

Excretion

Question 17

Metabolism of drugs

Answer 17

Lipophilic to hydrophilic > more polar, inactive, even toxic metabolites

Question 18

Site of drug metabolism

Answer 18

Liver
GI tract: with liver > first-pass effect
Kidneys
Skin
Lungs

Question 19

Cytochrome P450 induction

Answer 19

Superfamily of heme proteins

Induction by increased transcription by drugs:
Rifampin
Phenobarbital
Carbamazepine

These drugs enter hepatocytes and bind to xenobiotic receptors > active receptor translocate to the nucleus and bind to promoters of various enzymes

Question 20

Clinical consequences of enzyme induction

Answer 20

Drug increase its own/coadministered drug’s metabolism
Reduce plasma concentrations below therapeutic levels

Eg:
St. John’s wort induce CYP3A4

Question 21

Drugs inhibit cytochrome P450

Answer 21

Cimetidine
Erythromycin
Chloramphenicol
Grapefruit juice: inhibits felodipine metabolism

Less metabolism
Drug level reaches toxic concentrations

Question 22

Excretion pathways 2

Answer 22

Renal excretion: most common

Bile excretion: small number