Pharmacokinetics: Drug Absorption, Distribution, and Elimination (Pilch) - 080916 Flashcards
Drugs can be absorbed through which two routes and provide examples of both.
Enteral (via GI tract): oral, sublingual, rectal
Parenteral (bypass GI tract): intravenous (IV), intramuscular (IM), subcutaneous (SubQ), transdermal (skin), and inhalation (lungs)
How are drugs actively transported across the GI membrane?
Drugs bind to a protein carrier in the membrane with a high degree of structural specificity
Transport system linked to ATP consumption (can transport against a conc. gradient)
Transport system readily saturates - limits amount of drug that can be transported
What are the two classes of drugs that can be passively transported across the GI membrane (down conc. gradient)?
HYDROPHILIC DRUGS
- Water loving
- Possess a net charge - makes it difficult to pass through lipid membrane
- Only small hydrophilic drugs (MW
What is the Lipid-To-Water Partition Coefficient (P)?
What does the P value indicate?
Does a high P value equate to a high bioavailability of the drug?
P = Drug Conc. in Lipid Phase/Drug Conc. in Water Phase
Best predictor of drug entry into body
The higher the value of P, the more readily the drug will pass through the GI membrane (more absorption)
For high P value: NO. While drug absorption across membrane is critical, it doesn’t ensure bioavailability - b/c if that drug is highly metabolized during a first pass in the liver, bioavailability will be low.
What factors (4) are involved in drug absorption across GI membrane?
- Active Transport
- Passive Transport
- Lipid-To-Water Partition Coefficient (P)
- pKa of a drug
Many drugs are either weak acids or weak bases. Elaborate.
Acid: HA H+ + A-
Base: BH+ B + H+
Weak acids include any drug that has a carboxylic acid group on it (e.g., aspirin)
Weak bases include any drug that has an amino group (NH2) on it (e.g., morphine and atropine), as NH2 can combine with H+ to form NH3+
WA and WB can exist in either UNPROTONATED OR PROTONATED form.
**ONLY UNCHARGED DRUGS CAN MOVE PASSIVELY ACROSS GI MEMBRANES.
Why is pKa a very important predictor of drug absorption when we know the pH at the site of absorption?
can determine distribution of unprotonated to protonated drug
What is the pH partition hypothesis?
Distribution of a drug between two water compartments of the body that differ with regard to pH and are separated by a membrane
Distribution proceeds until, at equilibrium, the permeable (uncharged) form of the drug achieves equal conc. in both water compartments
At equilibrium, the total drug conc (uncharged + charged) will be higher in the compartment with the greater degree of pH-dependent ionization
Why are weak bases not absorbed into the plasma from the stomach but instead must wait until they enter the intestine?
pH is elevated in the intestine
at equilibrium, 100x more drug will be in the stomach than in the plasma, since BH+ cannot pass through membrane
Contrast lipid hydrophobicity to pH partitioning.
P = dictates absorption of non-acids/bases
pH partitioning dictates absorption of acids (acid or base will accumulate in the compartment where it is ionized the most)
What are the physiological factors governing drug absorption?
- Blood flow
Inc. blood flow = greater absorption (intestine has greater flow than stomach) - Surface area
Greater surface area = more absorption
Intestinal villi = 500x greater surface area for absorption than stomach –> intestine = most efficient area of drug absorption b/c of this + blood flow - Contact time and time to reach efficient area
Affliction that reduces this: diarrhea - Food
Absorption slowed by presence of food
(Drug is diluted by sheer presence of food)
What is oral bioavailability?
What factors decrease (oral) bioavailability?
Fraction (often given as a %) of orally administered drug that gains access to systemic circulation in a chemically unaltered form aka how much of what i swallow makes it to my bloodstream and stays there
Factors that decrease (oral) bioavailability:
1. First-pass hepatic transformation (metabolism)
- Hydrophilicity
If a drug is too hydrophilic, it will never gain access to the body - Metabolic and pH instability
Many rugs are altered by the enzymes in the GI tract or are altered by acidic pH -> reduce their bioavailability - Physical properties of the drug preparation
When two drug preparations differ to the point that their bioavailabilities also differ, they are said to be bioinequivalent (most common in hydrophobic drugs that are poorly water soluble… e.g. steroids)
Therapeutic inequivalence and index
Therapeutic inequivalence arises when bioinequivalence of two drug preparations lead to a difference in therapeutic outcome.
Most important determinant of whether bioinequivalence leads to therapeutic inequivalence = TI of prescribed drug.
TI = toxic dose (TD50)/effective dose (ED50)
When can use of a generic drug formulation be problematic?
- The two drug preparations are bioinequivalent.
2. The prescribed drug has a low TI (e.g., the anticoagulant drug warfarin)
Why is IV route used? (4 main reasons)
- For HYDROPHILIC DRUGS that are not well absorbed in GI tract and need to be administered directly into systemic circulation
- For METABOLICALLY LABILE DRUGS (i.e., insulin) that will be degraded by GI tract
- For INCREASED SPEED OF ACTION (anti-arrhythmic agents)
- For MAXIMAL CONTROL OF PLASMA CONCENTRATIONS, as IV administration allows one to reach a peak plasma conc, and then maintain it for an indefinite period of time
