Basic pharmacology
Routes of administration and systemic absorption of drugs:
Rate of systemic absorption determines onset, intensity and duration of action. Drug solubility and blood flow to the site of absorption are the most important factors:
Oral/enteral:
- most convenient & economic route of administration
- complicated by nausea/emesis & irregularities in absorption
- principle site of absorption is the small intestine
- GI mucosa and the liver contribute to extraction and metabolism of drugs
Oral/nasal transmucosal:
- drains to the SVC and/or VIJ and bypasses 1st pass hepatic metabolism
Rectal:
- highly unpredictable and irritant to rectal mucosa
- absorption is slow due to the small available surface area
- distal rectal administration will bypass 1st pass hepatic metabolism
- proximal rectal administration will not bypass 1st pass hepatic metabolism
Parenteral:
- includes subcutaneous, intramuscular and intravenous routes
- absorption is more reliable and complete
- IV administration avoids factors that limit systemic absorption by other routes and is a more comfortable way to administer irritant drugs
Neuraxial:
- epidural route is used to provide analgesia and anaesthesia
- significant systemic absorption may occur through the epidural venous plexus especially with lipid soluble drugs and continuous infusions (e.g. fentanyl)
- intrathecal or spinal administration rarely causes unwanted systemic effects
Distribution of drugs after systemic absorption:
Highly perfused tissues (heart, lungs, brain, kidneys and liver) receive a disproportionate amount of drug and initially sequester it from the plasma. Once plasma concentration falls following a bolus dose, drug will redistribute back into the plasma.
Following a bolus dose, plasma concentration first falls rapidly during the distribution phase and then more gradually during the elimination phase.
Remember that increasing an infusion of a drug to increase its desired effect should be preceded by a repeat bolus/load otherwise its effect will take ~5 half times!
Repeated large doses and/or prolonged infusions will saturate inactive tissues which will then act as reservoirs and prolong the duration of action of drugs.
Pharmacokinetic variables:
Volume of distribution (Vd):
- apparent volume a drug is injected into (calculated from dose and initial plasma concentration before any clearance)
- determinant of elimination half time (t½β)
- depicts the distribution characteristics of a drug in the body
- used to determine loading doses
- mainly influenced by physicochemical characteristics of the drug
Metabolism:
- hepatic microsomal enzymes are responsible for most drug metabolism
- hepatic extraction may be perfusion dependent (affected by hepatic blood flow) or capacity dependent (affected by ionisation and protein binding)
- lungs (eg. catecholamines), kidneys (e.g. morphine) and the GIT have considerable drug metabolising ability
- plasma cholinesterase and non-specific esterases are important in drugs containing ester bonds (e.g. esmolol, succinylcholine)
- Hoffman elimination is spontaneous non-enzymatic breakdown (e.g. cisatracurium)
Clearance (Cl):
- volume of plasma cleared of drug per unit time
- determinant of elimination half time (t½β)
- metabolism, excretion and non-organ clearance (e.g. ester hydrolysis) all contribute to clearance
- may be 1st order (proportional to plasma concentration) or zero-order (constant amount of drug cleared independent of plasma concentration)
Half times:
- time necessary for the plasma concentration of a drug to decrease by 50% (t½β ~ Vd/Cl)
- can be during distribution ( t½α) or elimination (t½β)
- plasma concentration does not always correlate with the clinical effect of the drug
- elimination half time determines the dosing interval to achieve steady state (~5 half times)
- context sensitive half time (CSHT) is the time necessary for the plasma drug concentration to decrease by 50% after ceasing a continuous infusion of a specific duration (context = duration of infusion)
Effect site equilibration time (ESET):
- delay between IV administration and onset of clinical effect reflects the delay in delivery of the drug to its site of action and subsequent dynamic response
- mainly determined by physicochemical properties of the drug
- important in determining dosing intervals when titrating to effect
Physicochemical properties of drugs:
Ionization:
- most drugs are present as both ionized and non-ionized molecules
- the proportion is determined by the pK of the drug and the pH of the surrounding fluid
- only the non-ionised drug is free to diffuse across membranes, be metabolized or be excreted
Protein binding:
- a variable amount of drug may be bound to various plasma proteins which affects distribution
- clinically significant protein binding is >90%
- acidic and neutral drugs generally bind to albumin and alkaline drugs generally bind to alpha1-acid glycoprotein
- only unbound drug is free cross membranes, be metabolised or excreted
Molecular size:
- small molecules diffuse much more readily than large ones
Lipid solubility:
- ability to physically diffuse through cell membranes (does not necessarily correlate with rapid onset of action)
Isomerism:
- mixtures often contain either inactive isomers or isomers that have different and/or adverse clinical effects (racemic and non-enantiopure preparations can be considered mixtures of different drugs)
Individual variability in dynamic response:
- the response (therapeutic and adverse effects) to many drugs varies widely among patients
- there is up to a five-fold range of plasma concentrations required to achieve the same pharmacologic effect in different individual patients
- there is up to a two-fold range of plasma concentrations required to achieve the same pharmacologic effect in the same patient using the same dosing regime
- absorption and bioavailability as well as variations in cardiac, renal and hepatic function contribute to inter- and intra-individual variability.
- enzyme activity (e.g. induction/inhibition) and genetic factors (e.g. fast/slow acetylators) also play a role
Effects of age and disease:
Renal disease will affect drugs excreted by the kidneys to an extent proportional to the degree to which the drug depends on renal excretion.
Hepatic disease alters plasma protein levels (decreased binding), increases Vd (ascites), reduces metabolism and may alter bioavailability (decreased 1st pass metabolism and/or porto-caval collaterals).
Neonates and infants:
- proportionally more water, larger intravascular volume and larger highly perfused organs
- immature blood-brain barrier makes them more sensitive to drugs acting in the CNS
- immature and inefficient hepatic metabolising capacity and lower plasma protein levels
- GFR < 10% of adult values will affect clearance
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