Transcript Pharmacokinetic Concepts

Principles of Drug Dosage, Formulation
and Routes of Administration
Principles of Drug Dosage

All drugs are potentially toxic depending on dose: the
aim is to produce a plasma concentration which is
effective but not toxic
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Minimum Effective Concentration The minimum plasma
concentration at which a therapeutic response
(pharmacodynamic effect) is obtained
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Maximum Recommended Concentration (or Minimum
Toxic Concentration) The maximum effective plasma
concentration, above which toxic side effects occur
Pharmacokinetic Concepts
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Pharmacokinetics encompasses the absorption,
distribution, metabolism, and excretion of a drug
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Pharmacokinetic parameters (ADME) usually determined
in volunteer studies in normal subjects
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The following concepts assist prescribers in making
therapeutic decisions; as before you are not expected to
be an expert but a general understanding will assist in
prescribing decisions
Pharmacokinetic Concepts

We will consider the following
pharmacokinetic concepts
1.
2.
3.
4.
Bioavailability
Volume of Distribution
Half-life
Clearance
Pharmacokinetic Concept 1:
Bioavailability
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The proportion of an administered dose of a
drug which reaches the circulation intact
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For an IV administered drug, the proportion is
100%, i.e. a factor of 1
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If the bioavailability of the oral form of the
same drug is 0.5, then only 50% of the original
dose has reached the circulation intact
Bioavailability contd.
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Propranolol has an oral bioavailability of about 0.05
because of ‘first-pass’ metabolism (100mg oral = 5mg IV)
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Digoxin oral bioavailability 0.7, morphine approx. 0.3
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So for morphine a 10mg iv dose might be equivalent to
approx. 30mg oral
Pharmacokinetics Concept 2: Volume
of Distribution (Vd)
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Reflects the extent of drug distribution
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Each drug has a unique volume of distribution
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Not a real (or physiological) volume, but an ‘apparent’
volume based on plasma concentration following a
known dose of the drug
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In general, high Vd reflects wide distribution to
the various organs and tissues, low Vd means that drug
stays in the plasma and ECF
Volume of Distribution contd.
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Warfarin (Vd 10L) binds tightly to plasma protein and
remains in the bloodstream; Gentamicin (Vd 15L) very
water soluble
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Chloroquine (Vd 13,000L) distributes out of the plasma
and binds tightly to cells in the retina
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Note that 13,000L is an “apparent volume” or it would
be a very big person!
Pharmacokinetic Concepts 3:
Elimination Half-life (t½)
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Half-life is associated with both
accumulation and elimination of drugs
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It is the time taken for the concentration of the
drug in the plasma to increase (accumulation)
or decrease (elimination) by half (50%)
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It is dependent on volume of distribution (Vd)
and clearance (Cl)
Half-life (t½) contd.
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Half life determines the time to reach constant
effective concentrations in the plasma and the
appropriate dosing interval to maintain that
concentration
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For drugs with a short half-life e.g. ferrous sulfate
dosing will need to be three or four times a day
(unless in a sustained release formulation – see
later); for drugs with a long half-life e.g. thyroxine,
dosing is once daily
Pharmacokinetic Concept 4:
Clearance
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The clearance (Cl) of the drug measures the ability
of the body to eliminate the drug
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It is expressed as volume/unit of time (e.g. mL/min)
and represents the volume of blood completely
cleared of the drug per unit time
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Major routes of elimination are the kidney (renal
clearance) and liver (hepatic clearance), and others
such as lung and sweat (minor sites)
Clearance contd.
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Clearance is a very important parameter in the
determination of maintenance doses
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Clearance of many drugs is affected by organ
function, especially the kidney
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Kidney function is estimated using the glomerular
filtration rate (GFR), expressed as mL/min
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Creatinine clearance (ClCr) is the most common
estimate used for GFR
Clearance contd.
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Creatinine is used to estimate renal function: it is a
metabolite produced at a relatively constant rate
(related to muscle mass), completely filtered by the
kidney, and not reabsorbed from the nephron
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If we measure appearance of creatinine in the urine
over a given period of time (e.g. 24h) we can estimate
ClCr and GFR
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Usually difficult to get a 24h urine sample, so we can
use equations or nomograms to get an estimate of ClCr
Clearance cont.
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Creatinine clearance often derived using serum
creatinine levels by nomograms or by the Cockcroft and
Gault equation:
Estimated ClCr = (140 – age in years) x (body wt in kg) x (1.04 females or 1.23 males)
(mL/Min)
Serum Creatinine (micromol/L)
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From the equation you will note that the estimate is based
on the patient’s age, weight, gender and their serum
creatinine levels
Clearance cont.
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Normal ClCr is above 100 mL/min
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Dose of many drugs may have to be
adjusted according to ClCr or other markers
of renal function
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Reference books have dose adjustments
based on ClCr, e.g. BNF
Classification of Renal Impairment
Level of impairment GFR (estimated from CrCl) (mL/min)
Mild
50-20
Moderate
20-10
Severe
<10
End Stage
<5
Adapted from Clinical Pharmacy and Therapeutics. 2nd ed. Walker and Edwards.
Formulation
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A novel active substance is of no practical use unless it
can be formulated into a dosage form that allows it to
be used in real patients
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Pharmaceutical companies may invest nearly as much
in developing the best formulation for a drug as in the
original discovery of the molecule (sometimes more)
Formulation cont.
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Very few drugs administered as pure substance
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Non-medicinal substances are used to enhance characteristics
such as appearance, stability, solubility, taste
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E.g. 100 mg ascorbic acid tablet contains 100mg of active, but
the tablet itself is much heavier
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Design and formulation needs to take into account physical,
chemical, and biological nature of all ingredients
Importance of Formulation
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To protect drug from atmospheric variations such as
humidity e.g. polished coating on tablets, sealing of
ampoules
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To protect oral doses from destruction due to gastric
acidity e.g. enteric coating
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To conceal bitter/salty or offensive tastes or odours
e.g. antibiotics, theophylline
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To suspend drugs that are insoluble e.g. paracetamol
mixture
Importance of Formulation contd.
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To provide clear liquid dose forms e.g. injectables,
syrups
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To provide rate-controlled drug release (prolonged or
extended effect) e.g. Ferro-Gradumet®
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To provide for drug to be given directly to
bloodstream e.g. intravenous injections or infusions
Oral Formulations
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Concentrate on oral because it is the main route
of administration
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Many different presentations e.g. tablets,
capsules, suspensions, solutions, mixtures,
emulsions, syrups, elixirs, linctuses, powders etc.
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Capsules and tablets can be formulated to
provide either immediate-release or prolongedrelease throughout the g.i. tract
ER Preparations contd.
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A variety of terms are used to describe these
formulations e.g sustained release (SR), long-acting
(LA), retard release (RETARD), extended release (ER),
controlled release (CR), extended release (XR) etc.
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Generally reserved for drugs with a relatively short halflife where frequent dosing would be required
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Ferrogradumet® is a sustained release form of ferrous
sulfate
ER Preparations contd.
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Advantages include prolongation of drug
action, reduction in dosing frequency,
reduction of side-effects, improved patient
compliance
Disadvantages include loss of flexibility in
dosing, dose-dumping in some cases,
technology failure (more in early days), may
be expensive, may be problematic in
poisoning cases
Different Iron Salts
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Oral iron preparations containing different
iron salts are available
Each has a slightly different side effect
profile, elemental iron content and cost
Iron salt
Amount
Iron Content
Ferrous fumarate
200 mg
65 mg
Ferrous gluconate
300 mg
35 mg
Ferrous sulfate
300 mg
60 mg
* Adapted from British National Formulary (BNF) 54th edition
Why should we know about routes of
administration?
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Other than if administered iv or intended for local
effects, drugs must enter the circulation before
distribution to intended sites of action
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So for many drugs the route chosen is about
controlling or overcoming absorption barriers
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Choosing the ‘optimal’ route of administration is a
very important decision in terms of overall
therapeutics – onset of action, dose, toxicity etc.
Principal Routes of Drug
Administration
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Injection (parenteral) – iv, im, sc etc.
Oral (includes enteral feeding) – absorption
principally from small intestine
Buccal/sublingual
Rectal
Inhaled
Transdermal
Topical (includes skin, eyes, ears etc.)
Injection Routes
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General:
- Intravenous
- Intramuscular
- Subcutaneous
Specialised:
- Intra-articular
- Epidural
- Intrathecal
- etc.
Intravenous Route
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Advantages include: no barrier to absorption; rapid
onset; can use loading/bolus doses; can use
intermittent infusion or continuous infusion; rapid
cessation of action
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Disadvantages include: patient may need to be
hospitalised or have specialist healthcare worker to
administer; cost; possibility of infection;
inconvenient/unpleasant for patient; mostly restricted to
water soluble drugs
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Numerous examples: gentamicin; morphine; heparin;
diazepam; iron sucrose
Intramuscular Route
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Advantages include no need to hospitalise; patient can
self-administer; can use depot injections; suitable for
water-insoluble drugs
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Disadvantages include painful; slower distribution;
slower onset of action; variable absorption; may need
higher dose; smaller volumes than iv
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Examples: Iron Polymaltose Complex; Depo-Medrol ®
(methylprednisolone); Modecate® (fluphenazine)
Subcutaneous Route
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Advantages include patient can selfadminister, suitable for implants; pain-relief
infusion devices can be used
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Disadvantages include slower onset of
action; irritation at the site; small volumes;
small doses
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Examples: insulin, low molecular wt heparin
Oral Route
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Most frequent and convenient route of administration
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Most medicines are administered by this route
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Tablets
Solution
Suspension
Powder
Capsule
Oral Route
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Tablets and capsules can be formulated for
‘immediate’ release or ‘extended’ release in
g.i. tract
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Tablets may be effervescent
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Main site of absorption is small intestine
Oral Route contd.
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Advantages include patient-controlled;
convenient/portable; comparatively low cost; a
variety of techniques to provide extended release
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Disadvantages include bioavailability concerns;
first-pass metabolism; relatively large doses
required; drug/food interactions; time lapse to effect;
compliance; dose frequency
Oral Route contd.
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Numerous examples:
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Multivitamins (powder, tablets, liquids)
Calogen (emulsion)
Paracetamol (suspension, tablets, capsules)
Morphine (solution, extended release tablets)
Phenoxymethylpenicillin (suspension, tablets)
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Dosing Considerations
– Short Bowel
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Consider a patient with a short bowel due to
surgery or disease
Which region of bowel is functioning?
Where is the prescribed drug absorbed?
E.g. Ferrogradumet® may not be suitable for
a patient with a short bowel, as the transit
time is too short for all the drug to release
and be absorbed. An immediate release
product may be more appropriate.