LEC 22 Drug Absorption, Distribution, and Elimination Flashcards
What are the major mechanisms of drug diffusion?
- Lipid diffusion (passive)
- Active transport
Less significant: Aqueous diffusion, endo/pinocytosis, facilitated diff.
What is Fick’s Law?
the actual equation and what everything means
- Concentration gradient (Co – Ci)
- Permeability coefficient, governed by lipid solubility, ionization
- Thickness of the biological membrane
- Area of the absorbing surface
What determines the aqueous solubility of a drug?
Electrostatic charge of the molecule
Degree of Ionization, Polarity
Which drugs cross membranes by lipid diffusion?
in relation to charge
Non-ionized
Non charged
Why are weak acids and weak bases able to cross biological membranes?
Both are uncharged and therefore more lipid soluble
Weak acids are (ionized or non-ionized) when protonated?
Non-ionized
Protonated form can cross membrane
Weak bases are (ionized or non-ionized) when protonated?
Ionized
Protonated form CANNOT cross membrane
What is the Henderson-Hasselbach equation?
The pH at which 50% of the weak acid or base is ionized is the what?
pKa
For acids, is a lower or higher pKa a stronger acid?
Lower
For bases, is a lower or higher pKa a stronger base?
Higher
At pH’s below the pKa, weak acids are mostly what?
Ionized or nonionized?
Nonionized
can cross the membrane
At pH’s above the pKa, weak bases are mostly what?
Nonionized
can cross the membrane
At pH’s above the pKa, weak bases are mostly what?
Nonionized
can cross the membrane
Lipid diffusion across membranes is directly proportional to what?
aside from ionization
Surface Area
What affects absorption of orally administered drugs?
- Physical form of drug (liquid vs solid) - solid takes longer
- Differences in pH of GI tract
- Differences in surface area
- Gastric emptying time
- Bacterial breakdown/Intestinal metabolism of drugs
- “First Pass Effect”
- Enterohepatic Circulation
Explain the “First Pass Effect”
- All drugs reach the liver before they get to the systemic circulation
- Drugs are absorbed in the small instestine and travel to liver via portal vein
- Low levels of drug in systemic circulation
Explain enterohepatic circulation.
- Drugs that are secreted into the bile are shuttled between the bile, intestine and liver.
- Very low levels reach systemic circulation
What advantage does sublingual administration have over oral administration of a drug?
The drug avoids the portal system
What are the advantages or rectal administration of a drug?
- Nausea & vomiting - pt can’t keep the drug down orally
- Some of the drug is absorbed systemically and some through portal vein - bc of rectal veins
What are the advantages of inhalation of a drug?
- Large tissue area for absorption
- Highly vascularized
- Bypasses first pass effect
- Good for local delivery to lung and airways
What are the advantages of injections?
- Reliability, precision, and compliance
- bypass problems of oral admin
What are the advantages of subcutaneous and intraperitoneal admin of drugs?
- slow and even distribution
- depot
- avoids first pass effect
What is the main advantage of intramuscular injections?
Speed
What are the advantages of intravenous admin of drugs?
- Fastest and most reliable method for achieving a desired blood concentration
- bypasses liver and gut
What is the bioavailability of a drug?
the fraction of the dose that is absorbed by a given route
What factors influence distribution of a drug?
- Regional differences in blood flow and tissue mass
- Solubility
- Barriers, especially blood brain barrier
- Binding - protein bound and ionized do not cross membranes, ionized can be ion trapped
- Transport mechanisms
The brain, spinal cord, kidney, liver, and heart together recieve about how much of total cardiac output?
70%
The brain alone recieves about how much of the total cardiac output?
20-25%
What are the important membrane barriers in the body with regards to drug distribution?
- Blood brain barrier
- Placental barrier
- Testicular barrier
Explain the concept of ion trapping.
- Weak bases are typically more nonionized in the blood (pH=7.4)
- Nonionized can diffuse across the nephron’s membrane into the urine
- The urine is more acidic (pH=6) and converts the base back to the ionized form d/t protonation
- Now that the base is charged, it cannot diffuse back across the membrane and is essentially trapped in the urine.
- More drug will be concentrated in the urine
Where are most drugs eliminated?
Kidney
What are the 3 most important processes involved in drug elimination in the kidney?
- Glomerular Filtration - only unbound drug in filtered here
- Active tubular secretion - membrane transporters in renal tubules
- Passive back diffusion (reabsorption) - nonionized weak acids and bases reabsorbed along with H2O
Why does tight drug binding to proteins reduce the drug’s glomerular filtration?
Proteins are not filtered
