Pharmacokinetics Flashcards
Barriers for oral drug to the CNS
The wall of the intestine
The walls of capillaries that perfuse the gut
The blood-brain barrier
Mechanisms of drug permeation
Aqueous diffusion = paracellular pathway
Lipid diffusion = transcellular pathway
Special carriers
Endocytosis and exocytosis = transcytosis
Absorption
Transfer of a drug fro its site of administration to the bloodstream
IV delivery: complete absorption
Other routes: partial absorption
First-pass effect
Oral drug is first metabolized in the gut wall and the liver before reaching systemic circulation
Enteral routes
Oral
Sublingual: bypass first-pass effect
Rectal: partial avoidance of the first-pass effect
Parenteral routes 4
Intravenous
Intramuscular
Subcutaneous
Intradermal
Other routes 4
Oral inhalation
Nasal inhalation
Topical
Transdermal
Factors that influence drug absorption
PH: uncharged is liposoluble Surface area: largest in intestine Blood flow: greater in intestine Contact time P=glycoprotein
Henderson-Hasselbalch equation
pH -pKa = log(unprotonated form/protonated form)
Ion trapping
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
P-glycoprotein
MDR1
Use ATP
Pump drugs out into the lumen, reduce drug absorption
Bioavailability
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
Determinants for drug distribution 4
Blood flow
Drug binding to plasma and tissue proteins
Capillary permeability
Drug hydrophobicity
Drug distribution to organs
First: liver, kidney, brain, and other well-perfused organs
Slower: muscle, most viscera, skin, fat
Blood-brain barrier
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
Drug elimination
Metabolism
Excretion
Metabolism of drugs
Lipophilic to hydrophilic > more polar, inactive, even toxic metabolites
Site of drug metabolism
Liver GI tract: with liver > first-pass effect Kidneys Skin Lungs
Cytochrome P450 induction
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
Clinical consequences of enzyme induction
Drug increase its own/coadministered drug’s metabolism
Reduce plasma concentrations below therapeutic levels
Eg:
St. John’s wort induce CYP3A4
Drugs inhibit cytochrome P450
Cimetidine
Erythromycin
Chloramphenicol
Grapefruit juice: inhibits felodipine metabolism
Less metabolism
Drug level reaches toxic concentrations
Excretion pathways 2
Renal excretion: most common
Bile excretion: small number
