2
Parenteral administration
• Intravenous: this route enables the entire dose to enter the systemic circulation reliably, unaffected by absorption or first- pass metabolism.
It is ideal when a high plasma concentration is needed quickly (e.g.
benzylpenicillin for meningococcal meningitis).
• Intramuscular: easier than the IV route (e.g. adrenaline (epinephrine) for anaphylaxis), but absorption is less predictable.
• Subcutaneous: this is ideal for self- administered parenteral drugs (e.g.
insulin, heparin).
• Transdermal patches: these enable a drug to be absorbed through the skin into the circulation (e.g. oestrogens, nicotine, nitrates).
Other routes of administration
• Topical: direct administration to the site of action (e.g. skin, eye, ear).
Achieves sufficient concentration at this site while minimising systemic exposure and adverse effects.
• Inhaled: administration allows direct delivery to the airways (e.g. salbuta- mol, beclometasone). However, a significant proportion of the dose may be absorbed from the lung or swallowed and can reach the systemic circu- lation. Correct use of a metered- dose inhaler is difficult for many patients. A
‘spacer’ device or a breath- powered dry powder inhaler can improve drug delivery. Nebulisers use pressurised oxygen or air to generate an aerosol from liquid drug that can be inhaled directly with a mouthpiece or mask.
Drug distribution
Distribution is the process by which drug molecules move into and out of the blood. It is influenced by molecular size, lipid solubility, plasma protein binding, affinity for surface- bound drug transporters and binding to molecular targets and other cellular proteins. Most drugs diffuse passively from the plasma to the interstitial fluid until the concentrations equalise. As the plasma concentration falls through metabolism or excretion, the drug diffuses back from the intersti- tium into the blood and is eliminated, unless additional doses enter the plasma.
Volume of distribution, Vd
This is the volume into which a drug appears to have distributed following intravenous injection. It is calculated as follows:
Vd= Dose given / Intial plasma concentration
Drugs that bind to plasma proteins (e.g. warfarin) have a Vd below 10 L;
those that enter the interstitial fluid but not the cells (e.g. gentamicin) have a Vd of 10 to 30 L. Lipid- soluble and tissue- bound drugs (e.g. digoxin) may have a Vd of greater than 100 L. Drugs with a larger Vd have longer half- lives than those with a smaller Vd, and take longer to reach steady state on repeated administration.
Drug elimination Drug metabolism
Metabolism is the process by which drugs are altered from a lipid- soluble form suitable for absorption and distribution to a more water- soluble form that is necessary for excretion. Some drugs, known as ‘prodrugs’, are inac- tive when administered but are converted to an active metabolite in vivo.
Phase I metabolism most commonly involves oxidation by the cytochrome P450 family of enzymes in the endoplasmic reticulum of hepatocytes.
Phase II metabolism involves combining phase I metabolites with an endogenous substrate to form an inactive conjugate that is much more water- soluble, thereby enabling renal excretion.
Drug excretion
Renal excretion is the usual route of elimination for drug metabolites of low molecular weight that have sufficient water- solubility to avoid tubular reabsorption. Drugs bound to plasma proteins are not filtered by the glom- eruli. Urine is more acidic than plasma, so some drugs (e.g. salicylates) become un- ionised in the kidneys and tend to be reabsorbed. Alkalina- tion of the urine can hasten excretion (e.g. after a salicylate overdose). For other drugs (e.g. methotrexate, penicillin), active secretion into the proximal tubule lumen is the main mechanism of excretion.
Faecal excretion is the predominant route for drugs with high molecular weight, those that are excreted in the bile after hepatic glucuronide conju- gation and those that are not absorbed after enteral administration. After biliary excretion, some lipid- soluble drugs are reabsorbed in the small intes- tine, returning to the liver via the portal vein (‘enterohepatic circulation’), thus prolonging the residence of the drug in the body.
Elimination kinetics
The net removal of drug from the circulation by metabolism and excretion is described as ‘clearance’, that is, the volume of plasma that is completely cleared of drug per unit time.
For most drugs, elimination is a high capacity process that does not become saturated, so elimination is proportional to drug concentration.
This results in ‘first- order’ kinetics, in which the time that it takes for the plasma drug concentration to halve (half- life, t1/2) is constant, causing an exponential decline in concentration (Fig. 2.4A). In this situation, a doubled dose leads to a doubled concentration at all time points.
For a few common drugs (e.g. phenytoin, alcohol), the elimination capac- ity is saturated within the usual dose range (‘zero- order’ kinetics). In this situation, if the rate of administration exceeds the maximum rate of elimina- tion, the drug accumulates progressively, with serious toxicity.
Repeated dose regimens
The goal of therapy is usually to maintain drug concentrations within the therapeutic range (see Fig. 2.2) over several days (e.g. antibiotics), or even for months or years (e.g. antihypertensives, lipid- lowering drugs). This requires the correct dose and frequency of administration.
As illustrated in Fig 2.4B, the time taken to reach therapeutic concentra- tions depends on the half- life of the drug. Typically, it takes approximately five half- lives to reach a steady state in which drug elimination equals drug administration, and drug concentrations stay within the therapeutic range.
This means the effects of a new dose of a drug with a long half- life (e.g.
digoxin, which has a half- life of 36 hours) may not be known for several days. In contrast, drugs with a short half- life (e.g. dobutamine) have to be given continuously by infusion but reach a steady state within minutes.
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Time (hours)
A constant fraction of drug is cleared in unit time
t1/2 = 8 hours C0
Plasma drug concentration
6 12 18 24
A
B
Loading dose Dose Dose
Dose Dose Dose Dose Dose
Subtherapeutic
Dose interval = 24 hours Time (days)
Plasma drug concentration
1 2 3 4 5 6
Therapeutic range Adverse effects
t1/2 = 30 hours
Fig. 2.4 Drug concentrations in plasma following single and multiple dosing. A Following a single IV dose, the time required for the plasma drug concentration to halve (half- life, t1/2) is constant throughout the elimination process. B With multiple dosing, the peak, average and trough concentrations rise progressively if each dose is administered before the previous dose is entirely cleared (black line). For most of the first 3 days, drug concen- trations are below the therapeutic range. This can be overcome by using a larger loading dose (red line) to achieve a steady state more rapidly.
For drugs with a long half- life, a large initial ‘loading dose’ can be given to achieve a therapeutic concentration rapidly, which is then maintained by subsequent doses. A steady state actually involves fluctuations in drug concentrations, with peaks after administration and troughs before the next dose. Manufacturers recommend dosing regimens that create, for most patients, troughs inside the therapeutic range and peaks low enough to avoid adverse effects. The optimal dose interval is a compromise between patient convenience and a constant level of drug exposure. Frequent administration (e.g. four times daily) achieves a smoother plasma concen- tration than once daily, but is much less convenient for patients. ‘Modified- release’ formulations allow drugs with short half-lives to be absorbed more slowly, reducing the oscillations in blood levels. This is especially useful for drugs with a low therapeutic index.