Pharmacokinetics- Absorption and Distribution

Question 1

Identify the factors that determine a given drug’s ability to cross biological membranes.

Answer 1

Molecular size (can be affected by drug binding to plasma proteins)
Lipid Solubility (estimated by oil:water partition coefficient)
Degree of ionization (affected by tissue pH, will influence lipid solubility)
Concentration gradient (created at site of administration)

Question 2

Describe the mechanisms by which drugs cross biological membranes (diffusion, transport, etc.).

Answer 2

Passive diffusion:
Aqueous diffusion/filtration: water soluble drugs through aqueous channels, limited capacity, generally for MW exo/endocytosis is of minor importance to drug passage.

Question 3

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 3

Oral:
Variable bioavailability
Relatively slow onset
Drug absorption affected by gastric emptying time
Affected by first pass metabolism

Rectal:
Variable bioavailability, but generally greater than oral route
Onset is not rapid
Useful when oral route is precluded by vomiting, or when patient is unconscious
Approximately 50% of dose with bypass liver, thus reducing first pass metabolism (compared to oral)
Absorption is irregular and incomplete

Sublingual-Buccal:
Bioavailability generally high
Onset of action within minutes
Venous drainage is direct to SVC, so protected from rapid hepatic first pass metabolism
Useful for drugs that are potent (<5 min
Route utilized for rapid onset of systemic drug effects.
Rapid rate of absorption due to large surface area and high blood flow in pulmonary tissue.

Transdermal:
75-100% bioavailability
Slowest speed of onset
Treats system conditions
Prolonged drug levels, 1st pass metabolism is avoided

Dermal (Topical):
Application via skin or mucous membranes fir local conditions
Minimal systemic absorption.

Question 4

Explain the influence of pH on the ionization of weak acid/weak base drugs.

Answer 4

Most drugs are either weak acids or weak bases. Acids become nonionized in an acidic medium, bases become nonionized in a basic medium. Nonionized forms are more readily absorbed, while ionized forms do not corss lipid membranes.

When the tissue pH is lower than the pKa of the drug–> more protons present, and the protonated form of the weak acid (nonionized-lipophilic) or weak base (ionized-hydrophilic) will predominate.

When the tissue pH is higher than the pKa of the drug—> relatively fewer protons present, unprotonated form of the weak acid (ionized-hydrophilic) or weak base (nonionized-lipophilic) drug will predominate.

Question 5

Henderson-Hasselbach equation

Answer 5

pH-pKa= log[non protonated A- or B]/[protonated form: HA or BH+]

Question 6

Explain the therapeutic consequences of anatomic “barriers” to distribution and selective accumulation of drugs.

Answer 6

Tissues with tight junctions between cells can limit movement of certain drugs (large size, protein bound, ionized, increased water-solubility), affecting pharmacokinetic processes. (e.g Blood brain barrier, GI mucosa, placenta, renal tubulues.
–> This requires drugs to pass through lipid membranes to or from this compartment and into or out of the blood.

Selective accumulation of certain drugs may occur in specific tissues (e.g. kidney, eye, lung, bone, ear, teeth), can harmful and beneficial effects.

Question 7

Describe how drug binding to plasma proteins can effect drug distribution and elimination as well as be a potential source of drug-drug interaction.

Answer 7

Protein binding reduces concentration of active, free drug (can limit fetal exposure), hinders metabolic degradation and reduces excretion (decreases elimination rate and increases half-life; acts as circulating drug reservoir that can prolong drug action), decreases volume of distribution, and decreases ability to enter CNS through BBB.

Drug-drug interactions:
Administration of 2nd drug displaces 1st drug from binding sites–> increases free levels of 1st drug.
Increases often samll and transient as free drug distributes to tissues and subject to metabolism and excretion.

Question 8

Bioavailiabilty (F)

Answer 8

F= Area under curve (route x, eg. oral)/ Area under curve IV
–> Area under curve from Cp vs time

Most info for bioavailability comes from oral dosing, therefor parenteral absorption of drug is likely to have different bioavailability. Therefore dosing asjustments should be made.

Question 9

Volume of distribution (Vd)

Answer 9

Cp= D/Vd
where, Cp= plasma concentration, D=dose, Vd= Volume of distribution

Vd will vary based body size (weight), composition (fat vs lean), and changes in protein binding.

Vd is the size of compartment necessary to account for total drug in body if present at same concentration in body as in plasma (Cp)

Vd is an apparent volume that represent that relationship between the dose of a drug and the resulting plasma concentration.