A/Prof. Ken Rodgers School of Life Sciences

Learning Objectives

  • Understand the effect of pH partitioning and lipid solubility on drug absorption
  • Describe factors affecting the absorption of drugs via oral administration especially first-pass metabolism
  • Understand the suitability, limitations and precautions of various routes of administration
  • Outline the concept of bioavailability

References

  • Rang HP, Dale MM, Ritter JM,  Flower R and Henderson G (2015) Pharmacology, 8th Edition, Churchill Livingstone, Sydney.
  • Absorption and distribution of drugs– Chapter 8

Drug Absorption

Absorbtion occurs mainly by diffusion through membranes

  • If a drug has a low lipid solubility it will be poorly absorbed from gut (eg tubocurarine)
  • Exception: Very small molecules may be able to penetrate poses in the mebrane (rare)
  • Exception: If a drug is similar to a natural molecule that is transported on a carrier it could be absorbed by carrier-mediated (pump) transfer (eg levodopa, fluorouracil)

Passage of Drugs Across Membranes

  • Cell membranes form barriers between aqueous compartments in the body
  • Cell membrane are relatively impermeable to ionised drugs
  • Special carriers and endo/exocytosis are probably not very important in drug absorption (few exceptions)
  • Main process is probably pH partitioning

pH Partitioning

pH Partitioning 

  • Most drugs, or their salts, are weak acids/bases
  • Thus the proportion of ionised to non-ionised drug depends upon the pH
  • Ionised drugs are not very lipid soluble – only non-ionised form of drug crosses membrane readily

pH Partitioning 

  • Biological fluids (blood, stomach and intestinal contents, urine) have different pH values
  • The pH of the solution will change the amount of drug that is ionised and will affect how and where drug is absorbed, distributed and how well it is excreted
  • For weak acids and weak bases the  % ionisation is determined by the Henderson-Hasselbalch equation

pH Partitioning

pH Partitioning

  • The degree of ionization is determined by the pKa of drug and pH of the solution
  • If the pH of the solution is the same as the pKa of the drug then  50% will be ionised and 50% will be non-ionised.
  • For acids:
    • pKa – pH = log ( [non-ionised] / [ionised] )
    • If pH = pKa then the log part of the equation = 0
    • We know that log 1 = 0 so  [non-ionised] / [ionised] must equal 1 so they must be the same
  • For bases:
    • pKa – pH = log ( [ionised] / [non-ionised] )

pH partitioning 4

  • Eg. aspirin (weak acid), pKa = 3.5

pH partitioning 5

  • Eg. pethidine (weak base), pKa = 8.6

Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between urine, plasma and gastric juice according to their pH differences. Numbers represent relative concentrations (total plasma concentration = 100). It is assumed that the uncharged species in each case can permeate membranes separating the compartments, and therefore reaches the same concentration in all three. Variations in the fractional ionisation as a function of pH give rise to the large total concentration differences with respect to plasma.

pH Partitioning 6

Applications of pH Partitioning

Applications of pH Partitioning 1

  • Alkalinisation of urine (NaHCO3): increases rate of excretion of weak acids (more ionised) eg phenobarbital

Applications of pH Partitioning 2

  • Acidification of urine (NH4Cl): increases rate of excretion of weak bases (more ionised)

Applications of pH Partitioning 3

  • Increasing plasma pH (NaHCO3): will shift weakly acidic drugs from the CNS to plasma (more ionised)

Summary: cellular barriers

  • To traverse cellular barriers (e.g. gastrointestinal mucosa, renal tubule, blood-brain barrier, placenta), drugs have to cross lipid membranes.
  • Drugs cross lipid membranes mainly by (a) passive diffusion
  • The main factor that determines the rate of passive diffusion across membranes is a drug’s lipid solubility (pH partitioning). Molecular weight is less important.

Summary: pH Partitioning

  • Many drugs are weak acids or weak bases; their state of ionisation varies with pH according to the Henderson-Hasselbalch equation.
  • Only the uncharged species (the protonated form for a weak acid, the unprotonated form for a weak base) can diffuse across lipid membranes; this gives rise to pH partition.
  • Weak acids tend to accumulate in compartments of relatively high pH (highly ionised)
  • Weak bases tend to accumulate in compartments of relatively low pH (highly ionised).
  • When the pH = Pka the weak acid/base is 50% ionised

Oral Administration & Absorption

The oral route of drug administration

  • Oral route (enteral), p.o. (per os)
  • 1. most common route
  • 2. usually safest
  • 3. most convenient
  • 4. most economical
  • Surface area, not pH partition, is main determinant of site of absorption – villi/microvilli in small intestine > stomach

Rapid oral absorption

  • So for rapid drug absorption, typically …
    • Take tablet with a large glass of water (eg 200 mL)
    • Take on an empty stomach eg at least half an hour before food (as long as gastric irritation is not a problem)

First-pass metabolism

  • 1. First-pass metabolism
    • Before entering the systemic circulation, blood leaving the GI tract passes through the liver
    • Thus, drugs that are highly metabolised by the liver may attain very low circulating levels relative to those attained after parenteral administration

Difficulties with Oral Absorption

First-pass metabolism

  • Difficulties with oral route 1
  • 1. First-pass metabolism
    • Before entering the systemic circulation, blood leaving the GI tract passes through the liver
    • Thus, drugs that are highly metabolised by the liver may attain very low circulating levels relative to those attained after parenteral administration

Irregular absorption

  • Difficulties with oral route 2
  • 2. Irregular absorption depends on stomach contents
    • delayed gastric emptying time
    • altered stomach pH due to food
    • decreased splanchnic blood flow in CHF
    • complex formation of drug with food products (eg tetracyclines with milk)

Absorption of alcohol

Absorption of alcohol

Difficulties with oral route 3

3. Gastrointestinal irritation eg aspirin
4. Low pH may inactivate certain drugs eg penicillins, insulin
5. Particle size (small = more rapid absorption)
(eg see digoxin graph)
6. Requires patient compliance

Bioavailability

Oral bioavailability

  • All the above factors influence oral bioavailability
    • Fraction of orally administered drug that reaches the systemic circulation
    • Two drugs with identical chemical composition that yield different blood concentrations and different effectiveness, differ in bioavailability (and are not bioequivalent)
    • Varies between individuals

Oral bioavailability

Overview of bioavailability

eg bioavailability of morphine via oral administration is only 20-33% when compared to IV administration

  • Intravenous: 100% by definition
    Intramuscular: 75 to <100%
    Subcutaneous: 75 to <100%
    Oral: 5 to <100%
    Rectal: 30 to <100%
    Inhalation: 5 to <100%
    Transdermal: 80 to <100%

Other forms of drug administration

Sublingual (SL)

  • Under the tongue
  • Rapid absorption
    • eg. glyceryl trinitrate
  • Avoids exposure of drug to gastric pH
  • Avoids first-pass metabolism
  • Taste could be an issue

Intravenous

  • Absorption pattern
    • Precise, accurate and potentially immediate effects (absorption phase is bypassed)
    • Suitable for large volumes and mixtures
  • Special Utility
    • Valuable for emergency use, permits titration of dose
    • Usually required for high molecular weight protein and peptide drugs (eg. tPA)
  • Limitations and precautions
    • Greater risk of adverse effects
      • High concentration attained rapidly
      • Risk of embolism
    • Must inject solutions slowly as a rule
    • Not suitable for oily solutions or poorly soluble drugs

IM and subcutaneous injection

  • Absorption pattern
    • Prompt absorption from aqueous solution, but slow and sustained from repository preparations
  • Suitable for:
    • Poorly soluble suspensions and slow release implants (sc)
    • Moderate volumes and some irritating substances (im)
    • Appropriate for self-administration (eg insulin)
  • Limitations and precautions
    • Not suitable for large volumes and pain and necrosis at injection sites for certain drugs (sc) eg thiopentone
    • Precluded during anticoagulant therapy (im)
    • May interfere with interpretation of certain diagnostic tests (eg. creatine kinase) (im)

Rectal (PR)       

  • Can be used for a local or systemic effect
  • Unconscious patients, children with poor IV access, if patient is vomiting
  • Easy to terminate exposure
  • Absorption may be variable
  • Good for drugs affecting the bowel such as laxatives / cathartics / drugs for ulcerative colitis

Spinal/Epidural       

  • Into spinal/epidural space for delivery of local anaesthetics/opioids for pain control
  • Preferred over GA in lower abdominal or lower limb surgery or in child birth

Topical (TOP) 1       

  • Mucosal membranes
    • Nasal, vaginal, etc.
    • zolmitriptan spray – migraine

Topical (TOP) 2      

  • Skin
    • 1. dermal (local)
    • 2. transdermal (systemic)
    • Stable blood levels
    • No first pass metabolism
    • Drug must be potent and lipophilic
      • scopolamine – motion sickness
      • oestradiol – hormone replacement
      • fentanyl – pain
      • clonidine – hypertension
      • nicotine – tobacco withdrawal
      • nitrates – angina
Topical applications