DD - Pharmacokinetics - Drug Absorption and Distribution

Question 1

1. Summarize the therapeutic advantages and disadvantages of the various routes of drug administration, especially with regards to bioavailability and rate of onset of effect.

Answer 1

• Use info about bioavailability to adjust dose based on route of admin; how much drug is reaching systemic circulation.
• Rate of absorption is an estimated value (Tmax or Cpmax) –> changes with drug formulation.
• Liquid preparations or rapid-dissolving tablets have increased rate of absorption; enteric-coated products and sustained-release preparations have decreased rate (this doesn’t change bioavailability!).

-Rate of absorption = IV = Inh > IM > SC > oral. ( thats the order)

Factors that affect absorption:

• drug solubility (formula must be hydrophilic to dissolve;
• molecule must be lipophilic to cross membranes),
• rate of dissolution,
• concentration of drug at site of admin,
• circulation at absorption site (changes with disease, exercise),
• area of absorbing surface.

-IV administration has F=100% because there is no absorption step. Most rapid onset; good for drugs with narrow therapeutic index. There is increased infection potential and it’s easy to quickly reach toxicity.

• Oral administration has F = 0-100% (lots of variability).
• Bioavailability depends on survival in GI environment (acidity, enzymes), ability to cross GI membranes
• (small, uncharged, lipid soluble things can cross tight junctions),
• and the efficiency of drug metabolism through the GI/Liver in 1st pass metabolism.
• Lose drug in the GI tract and in the liver so overall drug present in systemic circulation is less.
• Absorption from GI via lipid diffusion; mainly in small intestine.
• Increased GI motility = increased rate of absorption; can slow gastric emptying and absorption with food.
• Enteric-coated can protect sensitive stomach or protect drug from early degradation.
• Controlled release is good because you have less daily doses, can maintain drug effect over night, and eliminate toxic peaks; bad because of interpatient variations in Cp and dosage form failure that results in toxicity.
• Rectal = slow onset, variable bioavailability (> than oral). Good if oral not an option; bad because patients don’t like.
• Sublingual-buccal = fast onset; high bioavailability. Lipid soluble, potent drugs that don’t go through hepatic 1st pass metabolism.
• Intramuscular = bioavailability almost 100%, rapid onset. Absorption may be erratic and incomplete depending on drug solubility; depot forms have slower absorption (oil-based; these are slower acting –> sustained release). Can result in pain or tissue necrosis or contamination.
• Subcutaneous = F ~ 100%; slower, constant rate of absorption (based on particle size, protein binding, pH, etc.).
• Inhalation = fast onset, F ~ 100%. Very rapid onset of systemic effects due to large surface area and high blood flow. Effects depend on aerosolized particle size –> if too large, get side effects. Can also use inhalation for local effects, like in asthma. Aerosolized particles good for increasing local and decreasing systemic effects.
• Transdermal = apply patch to skin to treat systemic conditions and avoid 1st pass metabolism. Allows for prolonged drug levels, but drug must be potent.
• Topical drugs allow for localized application to treat local conditions. Very little systemic absorption.

Question 2

2. Explain the derivation and clinical relevance of the pharmacokinetic parameter bioavailability (F) and describe its use in designing dosage regimens->adjustment of dose for oral vs. parenteral administration.

Answer 2

Bioavailability (F): Adjustment of dose for oral vs. parenteral administration.
Bioavailability is the % of the initial dose reaching systemic circulation. Can use to adjust dose when the route is changed (ex: IV dose [or other parenteral] will be WAY lower than an oral dose since it’s bypassing the 1st pass metabolism). Oral bioavailability varies for many factors.

Question 3

3. Identify the factors that determine a given drug’s ability to cross biological membranes.
4. Describe the mechanisms by which drugs cross biological membranes (diffusion, transport, etc.).

Answer 3

-Gut/GI tract, BBB, and glomerulus all have tight junctions so drugs have to move through the cells into a different compartment (as opposed to between cells in peripheral circulation).

• Molecular size –> can be affected when drugs (reversibly bind to plasma proteins.
• Not bound = smaller size = increased passage through membranes.
• Lipid solubility –> estimated by oil: water partition coefficient; increased lipid solubility allows for increased membrane passage.
• Lipophilic drugs have to bind protein to move through the aqueous plasma, however. Greater reaction = increased lipid solubility.
• Degree/% ionization –> most drugs exist as weak acids and bases –> mixed as charged and uncharged.
• Their state is affected by tissue pH (which also influences lipid solubility).
• Non-ionized drugs pass through membrane better, so decreased % ionization = increased passage. (HH equation helps determine %.)
• Concentration gradient –> created at the actual site of administration.