Principles of Drug Dosage, Formulation and Routes of Administration

1
Principles of Drug Dosage, Formulation and Routes
of Administration
2
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
• Minimum Effective Concentration The minimum
  plasma concentration at which a therapeutic
  response (pharmacodynamic effect) is obtained
• Maximum Recommended Concentration (or Minimum
  Toxic Concentration) The maximum effective plasma
  concentration, above which toxic side effects
  occur

3
Pharmacokinetic Concepts

• Pharmacokinetics encompasses the absorption,
  distribution, metabolism, and excretion of a drug
• Pharmacokinetic parameters (ADME) usually
  determined in volunteer studies in normal
  subjects
• 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

4
Pharmacokinetic Concepts

• We will consider the following pharmacokinetic
  concepts
• Bioavailability
• Volume of Distribution
• Half-life
• Clearance

5
Pharmacokinetic Concept 1 Bioavailability

• The proportion of an administered dose of a drug
  which reaches the circulation intact
• For an IV administered drug, the proportion is
  100, i.e. a factor of 1
• 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

6
Bioavailability contd.

• Propranolol has an oral bioavailability of about
  0.05 because of first-pass metabolism (100mg
  oral 5mg IV)
• Digoxin oral bioavailability 0.7, morphine
  approx. 0.3
• So for morphine a 10mg iv dose might be
  equivalent to approx. 30mg oral

7
Pharmacokinetics Concept 2 Volume of
Distribution (Vd)

• Reflects the extent of drug distribution
• Each drug has a unique volume of distribution
• Not a real (or physiological) volume, but an
  apparent volume based on plasma concentration
  following a known dose of the drug
• In general, high Vd reflects wide distribution to
  
• the various organs and tissues, low Vd means
  that drug stays in the plasma and ECF

8
Volume of Distribution contd.

• Warfarin (Vd 10L) binds tightly to plasma protein
  and remains in the bloodstream Gentamicin (Vd
  15L) very water soluble
• Chloroquine (Vd 13,000L) distributes out of the
  plasma and binds tightly to cells in the retina
• Note that 13,000L is an apparent volume or it
  would be a very big person!

9
Pharmacokinetic Concepts 3Elimination Half-life
(t½)

• Half-life is associated with both accumulation
  and elimination of drugs
• It is the time taken for the concentration of the
  drug in the plasma to increase (accumulation) or
  decrease (elimination) by half (50)
• It is dependent on volume of distribution (Vd)
  and clearance (Cl)

10
Half-life (t½) contd.

• Half life determines the time to reach constant
  effective concentrations in the plasma and the
  appropriate dosing interval to maintain that
  concentration
• 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

11
Pharmacokinetic Concept 4 Clearance

• The clearance (Cl) of the drug measures the
  ability of the body to eliminate the drug
• 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
• Major routes of elimination are the kidney (renal
  clearance) and liver (hepatic clearance), and
  others such as lung and sweat (minor sites)

12
Clearance contd.

• Clearance is a very important parameter in the
  determination of maintenance doses
• Clearance of many drugs is affected by organ
  function, especially the kidney
• Kidney function is estimated using the glomerular
  filtration rate (GFR), expressed as mL/min
• Creatinine clearance (ClCr) is the most common
  estimate used for GFR

13
Clearance contd.

• 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
• If we measure appearance of creatinine in the
  urine over a given period of time (e.g. 24h) we
  can estimate ClCr and GFR
• Usually difficult to get a 24h urine sample, so
  we can use equations or nomograms to get an
  estimate of ClCr

14
Clearance cont.

• 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)
• From the equation you will note that the estimate
  is based on the patients age, weight, gender and
  their serum creatinine levels

15
Clearance cont.

• Normal ClCr is above 100 mL/min
• Dose of many drugs may have to be adjusted
  according to ClCr or other markers of renal
  function
• Reference books have dose adjustments based on
  ClCr, e.g. BNF

16
Classification of Renal Impairment
Level of impairment GFR (estimated from CrCl) (mL/min)
Mild 50-20
Moderate 20-10
Severe lt10
End Stage lt5
Adapted from Clinical Pharmacy and Therapeutics.
2nd ed. Walker and Edwards.
17
Formulation

• 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
• 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)

18
Formulation cont.

• Very few drugs administered as pure substance
• Non-medicinal substances are used to enhance
  characteristics such as appearance, stability,
  solubility, taste
• E.g. 100 mg ascorbic acid tablet contains 100mg
  of active, but the tablet itself is much heavier
• Design and formulation needs to take into account
  physical, chemical, and biological nature of all
  ingredients

19
Importance of Formulation

• To protect drug from atmospheric variations such
  as humidity e.g. polished coating on tablets,
  sealing of ampoules
• To protect oral doses from destruction due to
  gastric acidity e.g. enteric coating
• To conceal bitter/salty or offensive tastes or
  odours e.g. antibiotics, theophylline
• To suspend drugs that are insoluble e.g.
  paracetamol mixture

20
Importance of Formulation contd.

• To provide clear liquid dose forms e.g.
  injectables, syrups
• To provide rate-controlled drug release
  (prolonged or extended effect) e.g.
  Ferro-Gradumet
• To provide for drug to be given directly to
  bloodstream e.g. intravenous injections or
  infusions

21
Oral Formulations

• Concentrate on oral because it is the main route
  of administration
• Many different presentations e.g. tablets,
  capsules, suspensions, solutions, mixtures,
  emulsions, syrups, elixirs, linctuses, powders
  etc.
• Capsules and tablets can be formulated to provide
  either immediate-release or prolonged-release
  throughout the g.i. tract

22
ER Preparations contd.

• 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.
• Generally reserved for drugs with a relatively
  short half-life where frequent dosing would be
  required
• Ferrogradumet is a sustained release form of
  ferrous sulfate

23
ER Preparations contd.

• 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

24
Different Iron Salts

• 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
25
Why should we know about routes of administration?

• Other than if administered iv or intended for
  local effects, drugs must enter the circulation
  before distribution to intended sites of action
• So for many drugs the route chosen is about
  controlling or overcoming absorption barriers
• Choosing the optimal route of administration is
  a very important decision in terms of overall
  therapeutics onset of action, dose, toxicity
  etc.

26
Principal Routes of Drug Administration

• 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.)

27
Injection Routes

• General - Intravenous - Intramuscular -
  Subcutaneous
• Specialised - Intra-articular - Epidural -
  Intrathecal - etc.

28
Intravenous Route

• Advantages include no barrier to absorption
  rapid onset can use loading/bolus doses can use
  intermittent infusion or continuous infusion
  rapid cessation of action
• 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
• Numerous examples gentamicin morphine heparin
  diazepam iron sucrose

29
Intramuscular Route

• Advantages include no need to hospitalise
  patient can self-administer can use depot
  injections suitable for water-insoluble drugs
• Disadvantages include painful slower
  distribution slower onset of action variable
  absorption may need higher dose smaller volumes
  than iv
• Examples Iron Polymaltose Complex Depo-Medrol
  (methylprednisolone) Modecate (fluphenazine)

30
Subcutaneous Route

• Advantages include patient can self-administer,
  suitable for implants pain-relief infusion
  devices can be used
• Disadvantages include slower onset of action
  irritation at the site small volumes small
  doses
• Examples insulin, low molecular wt heparin

31
Oral Route

• Most frequent and convenient route of
  administration
• Most medicines are administered by this route
• Tablets
• Solution
• Suspension
• Powder
• Capsule

32
Oral Route

• Tablets and capsules can be formulated for
  immediate release or extended release in g.i.
  tract
• Tablets may be effervescent
• Main site of absorption is small intestine

33
Oral Route contd.

• Advantages include patient-controlled
  convenient/portable comparatively low cost a
  variety of techniques to provide extended release
• Disadvantages include bioavailability concerns
  first-pass metabolism relatively large doses
  required drug/food interactions time lapse to
  effect compliance dose frequency

34
Oral Route contd.

• Numerous examples
• Multivitamins (powder, tablets, liquids)
• Calogen (emulsion)
• Paracetamol (suspension, tablets, capsules)
• Morphine (solution, extended release tablets)
• Phenoxymethylpenicillin (suspension, tablets)

35
Dosing Considerations Short Bowel

• 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.