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

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

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

Pharmacokinetic Concepts

We will consider the following pharmacokinetic concepts

1. Bioavailability

2. Volume of Distribution

3. Half-life

4. Clearance

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

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

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

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!

Pharmacokinetic Concepts 3:Elimination 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)

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

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)

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

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

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 patient’s age, weight, gender and their serum creatinine levels

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

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

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)

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

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

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

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

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

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

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

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.

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.)

Injection Routes

General: - Intravenous - Intramuscular - Subcutaneous

Specialised: - Intra-articular - Epidural - Intrathecal - etc.

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

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)

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

Oral Route

Most frequent and convenient route of administration

Most medicines are administered by this route– Tablets– Solution– Suspension– Powder– Capsule

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

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

Oral Route contd.

Numerous examples:

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

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.