Absorption

• The bioavailable fraction is the fraction of a drug that reaches the circulation when compared to the same dose given via the intravenous route (measured from 0-1)

• Bioavailability is also the ratio of the area under the concentration-time curve (AUC) of the stated route compared to the IV route
• E.g. oral bioavailability = AUC_oral / AUC_IV
• The AUC of a route's concentration vs. time graph is found by integration


• Absolute bioavailability is as described above: the ratio compared to IV administration
• Relative bioavailability is used for drugs that cannot be administered IV
• In such cases the calculation uses a standard formulation of the drug and compares other routes/formulations against this e.g. capsule vs. tablet

• Route of administration
• Pharmaceutical properties
• Rapid absorption from small particles, liquids and immediate-release formulas
• Delayed absorption from large particles, enteric-coated or modified-release formulas
• Physicochemical interactions e.g. calcium reduces tetracycline absorption, orange increases absorption of iron

• Pharmacogenetics
• Individual pharmacokinetics e.g. degree of first pass metabolism, hepatic function etc.

• First pass metabolism occurs in drugs absorbed from the GI tract, which pass via the portal vein to the liver before entering the hepatic and thereafter systemic circulation
• A proportion of the drug is metabolised during its passage through the liver, reducing the bioavailable fraction
• Drugs that have a high first pass metabolism include:
• GTN
• Lidocaine
• Aspirin
• Morphine
• Midazolam

• The extraction ratio is the fraction of a drug removed from the blood by an organ with each pass through that organ
• For example, for an oral drug:

Bioavailable fraction = Fraction absorbed x fraction remaining after gut and hepatic metabolism

F_B = F_A x F_G x F_H

• Hepatic extraction ratio depends on:
• Hepatic blood flow
• Hepatocyte uptake of the drug
• Metabolic capacity of the hepatocyte for the drug (dependent on the Michaelis constant of the enzyme, the [substrate] at which the enzyme is working at 50% maximal rate)


• Drugs typically fall into three groups:
1. Flow dependent, protein binding independent
2. Capacity dependent, protein binding dependent
3. Capacity independent, protein binding independent

• E.g. propofol, lidocaine
• The free drug is rapidly removed from plasma
• Therefore protein-bound drug is released
• The drug is rapidly metabolised within the hepatocyte
• This establishes a concentration gradient between the plasma and hepatocyte
• The drug's metabolism and extraction ratio is therefore highly dependent on hepatic blood flow and independent of protein binding

• E.g. phenytoin, diazepam
• The metabolism is limited by the metabolic capacity of the hepatocyte
• If protein binding is altered, then the [free drug] increases
• Initially, there is increased hepatocyte uptake but unchanged metabolism
• Once enzymes are saturated, intracellular levels increase and the concentration gradient disappears
• Hence the plasma free concentration rises and may cause side effects
• The drug's metabolism and extraction ratio is therefore influenced by metabolic capacity and protein binding, not hepatic blood flow

• The total amount of drug metabolised is unaffected by hepatic blood flow or protein binding, and is largely dependent on enzymatic capacity to metabolise the drug

• Absorption takes place through gut mucosa, and is therefore impacted by gut motility and GI pathology
• Only unionised drugs and those with specific transport membranes make it through the lipid membranes of the gut
• The pH of the gut varies from stomach (acidic pH, acidic drugs unionised) through to duodenum (alkali pH, basic drugs unionised)
• There is variable absorption of drugs at different sites
• The salts of permanently charged drugs e.g. vecuronium, glycopyrrolate are not absorbed from the GIT
• In practice most drugs are absorbed in the small intestine due to its high surface area
• In general, oral route has the lowest bioavailability

• Rapid onset routes due to absorption through mucous membrane
• Higher bioavailability vs. oral as avoid first pass metabolism in the portal tract
• E.g. GTN, nifedipine SL, buccal midazolam

• Higher availability vs. oral as avoid first pass metabolism in the portal tract
• Small surface area vs. GI tract means slower absorption
• Considered for local effects (e.g. steroids in IBD) or systemic effects (diclofenac PR)

• Faster speed of onset than oral
• Bioavailable fraction approaches 1.0 as avoids problems associated with oral route
• Absorption depends on local perfusion
• Delayed absorption following IM administration:
• Reduces drug efficacy and multiple doses may therefore be given
• When perfusion is restored, there may be a sudden rise in plasma concentrations to toxic levels
• Administration may cause pain, haematoma or abscess

• Certain drugs are well absorbed sub-cut. e.g. LMWH
• May be indicated if compliance is an issue
• Absorption depends on local perfusion and a similar issue as with IM administration may occur
• E.g. subcutaneous insulin in the critically unwell patient

• Can be used for topical effect e.g. steroids, local anaesthetic
• Can be used to avoid first-pass metabolism and therefore increase bioavailability e.g. fentanyl, nitrates
• Highly lipid soluble drugs favour transdermal absorption e.g. fentanyl
• Absorption depends on local perfusion
• Can use patches to create a smooth pharmacokinetic profile i.e. slow, constant release of drug


• Iontophoresis is a special type of transdermal application whereby an electromotive force is used to drive medication through the stratum corneum of the skin
• It is used therapeutically e.g. in hyperhidrosis
• It is used diagnostically e.g in CF; pilocarpine iontophoresis is used to stimulate sweat glands

• Can be used for local effect e.g. bronchodilators, inhaled nitric oxide, adrenaline
• Can be used for systemic effect e.g. volatile agents have site of action in the CNS
• The large surface area for absorption can lead to rapid rises in systemic concentration and rapid onset of action at distant effector sites
• The particle size and method of administration determine whether a drug reaches just the upper airways or alveolus too; only droplets <1μm in diameter reach the alveolus

• Used to provide regional anaesthesia and analgesia
• E.g. LA, opioids, ketamine, clonidine
• Speed of onset of LA determined by portion of unionised drug i.e. pKa
• E.g. lidocaine has faster onset than bupivacaine
• Addition of NaHCO₃ will increase local pH, increasing the unionised fraction and reducing onset time
• Significant amounts may be absorbed into systemic circulation, causing side effects e.g. LA toxicity, opioids

• Amount of drug required is less than epidural route
• Little reaches systemic circulation and therefore rarely causes direct drug side-effects
• Speed of onset determined by:
• Volume used
• Speed of injection
• Type of solution and positioning (e.g. use of heavy bupivacaine)