Lent

Supervision 1: Introduction to Pharmacokinetics – Summary

• ADME
o Absorption
o Distribution
o Metabolism
o Elimination
• Routes of administration and their advantages/disadvantages
o IV injections and Infusions
§ These are quick and typically cause an immediate effect
§ When drug is administered by injection, its concentration in plasma is immediately high
and, by definition, its bioavailability is 1 because the drug is immediately in systemic
circulation
• Bioavailability, F, can be defined as the fraction of administered drug that gets
into systemic circulation
§ Immediate effect is sometimes needed – big advantage
• Injection of the anti-convulsant diazepam to stop seizures or injection of
haloperidol to sedate a psychiatric patient in crisis

•
§ Another advantage is control
• The injection or infusion can be stopped if side effects develop, or its dose can be
reduced
§ Lastly, it allows accurate dosing
• This is especially when the therapeutic window is narrow (e.g. with cytotoxics
in cancer)
• The required concentration in plasma can be calculated using pharmacokinetic
parameters of the drug and patient’s parameters
o In other routes of administration, this advantage is missing because
everyone gets the same dose but then it depends on inter-individual
variations in absorption, metabolism and distribution that determine the
effective concentration of the drug in plasma
• Therapeutic window = the difference between the effective drug concentration,
typically called ED50 (the dose which produced a beneficial effect in 50% of
tested population), and the toxic drug concentration, typically called LD50 (the
dose which caused death in 50% of the tested population)
 o
§ Disadvantages
• Requires skill to administer doses, e.g. admission to a day therapeutic unit for
cannulation and drip (chemotherapy, biologics)
• Infusions require extra equipment
• Risk of infection to injection site
• High initial concentration with injection can irritate veins and lead to phlebitis
• Painful for the patient
o Intra-Muscular (IM) and Sub-cutaneous (SC) injections
§ The absorption of a drug into systemic circulation will be proportional to the local
concentration of the drug in muscle/subcutaneous tissue and the blood flow to that
tissue
• Hence, the rate of absorption is increased when the solution is distributed
throughout a large volume of the muscle and dispersion of the drug is
enhanced by massage of the injection site
• The greatest blood flow is in the deltoid, followed by vastus lateralis and then
gluteus maximus
o Systemic absorption rates will be increased in all of those sites following
exercise but shock, heart failure and all other conditions that decrease
muscle blood flow will negatively affect the transport of the drug from
the injection site
§ The drug can be either soluble or precipitate (forms a solid)
• If soluble, its amount remaining at the local site will decline and so will the local
concentration and thus the rate of absorption into systemic circulation
• If it precipitates, it forms a constant solid supply so local concentration remains
high
o Some drugs crystallise when given IM (phenytoin, diazepam) because
they are not sufficiently water soluable and so poor absorption occurs
when these are given IM
§ Cutaneous blood flow is lower than in muscle so absorption is slower
• For example, adrenaline used in conjunction with a local anaesthetic increases
the duration of local anaesthetic at site of injection (thus reducing absorption)
because it constricts subcutaneous vessels
• Good example of a sustained effect from SC injections is injection of insulin
o Different rates of absorption are being achieved by different insulin
preparation
o Similar use for oestrogen pellets in HRT
§ Advantages:
• Slow, prolonged, constant absorption can be achieved
• Can be used for drugs not available orally
 • Large amount can be administered so it can increase compliance, e.g. depot
injections of fluphenazine in psychiatric patients or medroxyprogesterone
acetate injection used as a contraceptive depot
§ Disadvantages:
• Rate of entry into systemic circulation can be unpredictable
• Can be painful
• Absorption very slow if drug precipitates
o Transdermal absorption
§ Drugs penetrate the skin, governed by their lipid/water partition coefficients that are
effectively derived from their hydro/lipophilicity
§ This is a slow, and variable route but yet again, bypasses the liver which would have
metabolized the drug before it gets into systemic circulation
§ This can include topical application (creams, gels, ointments) or transdermal patches
(for HRT for example, or fentanyl patches for analgesia)
• Various factors affect absorption:
o Age – infant skin better than old
o Skin condition – rashes, diseases
o Region of the skin
o Hydration of the skin
o Vehicle used in creams and ointments
o Surface area to which the drug is applied – infants, for example have a
large SA: volume ratio
o Inhalation
§ Drugs can be inhaled as aerosols for their local effects on bronchioles
• This is mainly beta-2 adrenoceptor agonists (salbutamol), steroids
(dexamethasone), muscarinic receptor antagonists (ipratropium) used in the
treatment of asthma or COPD
• Nebulized antibiotics can also be used
o For many of these drugs, limitation of systemic absorption is desirable
o Ipratropium, for example, would have atropine-like side effects
(decreased salivation, reduced GI motility, urinary retention) so it helps
that it is highly polar and poorly absorbed across the thin membrane of
the alveoli
• Large fraction of inhaled salbutamol may also be swallowed, but it does not have
systemic side effects typically because it is inactivated in the gut wall
o A systemic side effect would be fine tremor
§ Lungs are ideally suited for absorption from the gas phase; however,
• Total respiratory surface area is very large and only about 60mL of blood is
circulating through capillaries creating a high concentration gradient for
diffusion of gases across alveoli such as general volatile anaesthetics
o Other routes
§ Buccal, sublingual (avoid first pass), rectal (first pass effect slightly bypassed), nasal,
intravaginal, eye drops, ear drops, intrathecal injections, extradural
o
o Oral route and first-pass effect

§
§ Most common route as it is easy and convenient for the patient
§ Systemic effect takes place due to absorption through the gut wall and entry into portal
circulation into the liver, and from there into systemic circulation
• Absorption from the gut
o Passive diffusion
§ Most important as non-polar lipophilic agents are well absorbed
from the gut, mainly from the small intestine because of the large
absorptive surface provided by the villi
o Active transport
§ Requires a specific carrier and typically used for polar
substances, such as those that mimic the structure of naturally-
ocurring polar substances such as sugars, vitamins, amino-acids
(L-DOPA, MTX, Lithium)

o Other factors that influence absorption from the gut
§ Surgical interference with gastric function can reduce absorption
of several drugs
§ Disease of the GI tract such as coeliac disease, or cystic fibrosis
 § Presence of food as food and drink dilute the drug and can bind
it, or alter gastric emptying or increase mesenteric and
portal blood flow
§ Drug metabolism by intestinal flora
• First-pass effect
o An orally-administered drug may be inactivated both within the gut
lumen by gastric acid (think of Henderson – Hasselbach equation),
digestive enzymes, or bacteria
o Drugs can be metabolized by enzymes in the liver (cytochrome P450
enzymes – CYP450) which therefore significantly affects the effective
concentration of drugs in systemic circulation
§ This is called the first-pass effect
• Orally absorbed drugs therefore typically have a bioavailability of less than 1
o Bioavailability can be measured experimentally by measuring
concentration v. time curves following administration of the preparation
by the intended route (e.g. orally) and the same dose given IV (the gold
standard for absorption as its bioavailability is, by definition, equal to 1)

o
o We will discuss what AUC means a bit later in the course
o If two drugs (can be different generic preparations) are given orally and
produce the same bioavailability of the active ingredient, they are said to
be bioequivalent; however, that does not imply the exact same kinetics
of absorption but that the PK parameters are unlikely to make a clinical
difference
o Drugs can be given as prodrugs to increase bioavailability
§ Drug molecule is modified chemically to form a compound which
is better absorbed and from which the active drug is liberated
after absorption
 §
• Drug distribution – binding to plasma proteins
o It is important to realize that once drug is in systemic circulation it is not circulating mostly as a
free drug but a substantial portion of it is bound to plasma proteins, such as albumin
§ In every modeled ‘compartment’, the drug will exist in its bound form and its free form
§ Note that only the free form can cross compartments, which is needed for the drug to
actually get from site of injection to site of drug action (receptor)

•
• Total plasma concentration will equal the concentration of free and bound drugs
added together
• A drug that is bound to plasma protein cannot be effective, because it cannot get
to the site of action; however, as the [bound] and [free] fractions exist in
equilibrium, as soon as some of the free drug leaves one compartment to the
next one, the position of equilibrium will be shifted and more drug will
dissociate from the plasma protein to become a free drug
• Drugs can compete for binding sites at plasma proteins and therefore co-
administering drugs may lead to pharmacokinetic interactions because the
free concentration of one drug will be made higher by co-administration of the
drug that binds to the same site on the protein
o Similarly, if the levels of plasma proteins change, e.g. in liver disease, the
free concentration of a drug that binds to them extensively will increase
§ Most weak acids bind to albumin, most weak bases bind to alpha-1 acid
glycoprotein







 o Apparent volume of distribution

§
• These are the values for an average 70kg man
§ The apparent volume of distribution is the fluid volume in which drug appears to be
dissolved based on the amount absorbed and final plasma concentration (sampled
from the plasma); units are given in Litres

•
• For example, 10mg of IV drug X was given to a patient and it was then
discovered that the plasma concentration was 0.05mg/mL, calculate Vd
o 10/0.5 = 200mL = 0.2L
o 0.5L of Vd tells you that the drug does not distribute very well, and
because you know that 3L is the volume of plasma it is likely that this
drug only distributes in plasma, and thus is highly likely a polar drug
with extensive binding to plasma protein
o If the drug was sequestering into fats easily (hydrophobic), it would
mean that the sampling would only discover a very small concentration
in plasma and therefore a massive Vd
§ If 10mg of drug Y was given and Cp was later found to be
0.00005mg/mL then Vd = 200000mL = 200L which is higher
than the total body water
§ Because these volumes are not physiological volumes, this
volume is referred to as apparent volume