Pharmacokinetics

• Pharmacokinetics - what the body does to the drug e.g. absorption, metabolism, excretion
• Pharmacodynamics - what the drug does to the body e.g. therapeutic or adverse effects, interaction between drug and cells, relationship between drug concentration and drug effect
• Understanding pharmacokinetics helps prescribers optimise medication regimens for individual circumstances e.g.

  • adjustment of dose, frequency or route of administration
  • correct interpretation of therapeutic monitoring
  • explain why some patients respond differently to same drug
  • improve safety and efficacy
• Bulk flow transfer

  • long distance distribution through blood
  • unaffected by chemical properties
• Diffusional transfer within body compartments

  • aqueous diffusion within well-stirred compartments
  • diffusion coefficient D is proportional to 1/sqrt(MW)
• Diffusional transfer between body compartments

  • transfer through non-aqueous barriers
  • transmembrane
  • passive diffusion
  • carrier molecules (GI tract, renal tubule, biliary tract, BBB)
  • facilitated diffusion
  • active transport
  • pinocytosis
  • vascular endothelium (transmembrane fenestrations)
• Cell membranes are mainly lipoproteins. Lipophilic drugs diffuse across membranes more easily.
• Lipid solubility is described using logP. Higher logP = more lipophilic
• Clinical implications of lipid solubility

  • absorption rate
  • tissue penetration
  • e.g. potential for CNS effects as crosses BBB - atenolol has fewer adverse CNS effects from metoprolol
  • limited renal excretion
  • accumulates in fat stores
  • binds to proteins in plasma
• Most drugs are weak acids or bases
• Weak bases

  • BH <-> B + H+
  • pKa = pH + log10 ([BH+]/[B])
• Weak acids

  • AH <-> A- + H+
  • pKa = pH + log10 ([AH]/[A-])
• Only unionised species are lipid soluble. Highly ionised drugs are less lipid soluble.
• Degree of ionisation depends on

  • dissociation constant (pKa) of drug (the pH at which drug is 50% ionised)
  • local pH
• Ionisation affects distribution between aqueous compartments of differing pH (the pH partition)
• Acids become more ionised in basic environments (and vice versa) and then cannot escape that compartment
• Many drugs are reversibly bound to circulating proteins e.g. albumin (acids), glycoproteins (bases), lipoproteins, globulins (hormones).
• Only unbound drug is active and has pharmacological effect - binds receptors, crosses membranes, metabolised, excreted etc.
• Drug-protein complex acts as a reservoir, with bound and free drug existing in equilibrium. Removal of free drug leads to liberation from bound state (and vice versa).
• Amount of binding is dependent on various factors:

  • free drug concentration
  • affinity for binding sites
  • protein concentrations
• Changes in binding can affect distribution
• Reduction in protein binding occurs with

  • renal insufficiency
  • hypoalbuminaemia
  • pregnancy (3rd trimester)
  • displacement by other drugs
• Drugs with high % bound are susceptible to displacement. Drugs occupying >50% sites may cause displacement. Changes in protein binding are important for highly bound drugs
• Phases of drug disposition

  • absorption
  • distribution
  • metabolism
  • elimination
• Enteral drug absorption

  • sublingual/buccal
  • oral
  • rectal
• topical drug application

  • skin
  • cornea
  • nasal
• Injection

  • intravenous
  • intramuscular
  • subcutaneous
  • other e.g. joints, CSF
• Advantages of oral drug absorption

  • easy
  • preferred by patients
  • slow-release preparations may be available to extend duration of action
  • drugs can be formulated in such a way as to protect them from digestive enzymes, acid etc.
• Disadvantages of oral drug absorption

  • unsuitable in patients who are uncooperative, strictly nil by mouth, are vomiting profusely or have ileus
  • most orally administered drugs are absorbed slowly
  • unpredictable absorption due to degradation by stomach acid and enzymes
• Advantages of rectal drug absorption

  • good absorption - the haemorrhoidal veins drain directly into the inferior vena cava, avoiding hepatic first pass metabolism
• Disadvantages of rectal drug absorption

  • may not be suitable after rectal or anal surgery
  • some patients dislike suppositories
• Advantages of subcutaneous or intramuscular drug absorption

  • good absorption, especially for drugs with a low oral bioavailability
  • onset is more rapid than other routes
  • depending on formulation can have very long duration of action e.g. depot antipsychotics and contraceptives
• Disadvantages of subcutaneous or intramuscular drug absorption

  • absorption may still be unpredictable if peripheries are poorly perfused
  • injections hurt, cause bruises and frighten children and needle phobics
• Advantages of intravenous injection

  • dependable and reproducible effects
  • entire administered dose reaches the systemic circulation immediately - the dose can be accurately titrated against response
• Disadvantages of intravenous injection

  • requires a functioning cannula
  • more expensive and labour intensive than other routes
  • cannulation is distressing to some patients, especially children
  • cannulae are prone to infection
  • IV injection of drugs may cause local reactions
• Advantages of topical drug absorption

  • easy
  • non-invasive
  • high levels of patient satisfaction
• Disadvantages of topical drug absorption

  • most drugs have high molecular weight and are poorly lipid soluble, so are not absorbed via skin or mucus membranes
  • very slow absorption
• Advantages of inhaled drug absorption

  • very rapid absorption due to huge surface area of respiratory endothelium
  • bronchodilators and inhaled steroids can be targeted to lungs with low levels of systemic absorption
• Disadvantages of inhaled drug absorption

  • bioavailability depends on patient's inhaler technique and the size of drug particles generated by the delivery technique
• Oral drug delivery

  • convenient
  • simple
  • self-administered
  • ideal for long-term treatment of less acute illnesses