Drug handling: Introduction
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☞ Why this subject matters...
Many clinical problems require a basic understanding of pharmacokinetics. These range from predicting how quickly a patient will respond to a change in drug regimen, to estimating doses in patients at extremes of weight or age. This tutorial covers the key terminology and some practical tips on problem solving in clinical practice.
Explaining some concepts
We start by describing the difference between two similar-sounding words, that you'll need to be confident you understand...
Pharmacokinetics
The time course of absorption, distribution, metabolism and excretion of a medicine. Think of this as: ‘what the body does to the medicine’.Pharmacodynamics
The biochemical and physiological effects of medicines and their mechanisms of action. This includes all the actions of a medicine not just the desirable ones – so it's about side effects too. To help you remember the difference from pharmacokinetics you could say pharmacodynamics is ‘what a medicine does to the body’.Bioavailability (F)
The fraction of a medicine's dose that reaches the systemic circulation as intact drug. It depends on how well the drug is absorbed and how much is removed by the liver during ‘first-pass clearance’. Poorly absorbed medicines and/or those that undergo extensive hepatic metabolism will have a low bioavailability (e.g. oral lidocaine); medicines that are well absorbed and/or are not metabolised significantly in the liver will have higher bioavailability (e.g. oral warfarin). Medicines that are administered intravenously have a bioavailability of 100%.Volume of distribution (Vd)
A hypothetical volume that relates the concentration of drug in the plasma to the total amount of drug in the body. It illustrates the distribution of the drug in a patient. The equation for the volume of distribution is expressed as follows:
Vd(L) = Total amount of drug in the body (mg) ÷ Plasma drug concentration (mg/L)
The volume of distribution is determined by physiological factors such as the size of the patient. For example, a 160kg young male athlete would be expected to have a larger Vd than a 40kg older female patient aged 83 because his blood volume and tissue size will be larger.
Pharmacodynamic factors such as the affinity of the drug for the tissues compared with the plasma may also affect the Vd. Digoxin is very tightly bound by the tissues and not held in the plasma: the drug appears to be dissolved in a large volume and thus the Vd is large (6L/kg).
In contrast, warfarin is held in the plasma by proteins and does not distribute to the tissues. The Vd in this case is smaller and approximates to the actual blood volume (approximately 0.08 – 0.27L/kg).
Vd helps to determine the loading dose of a drug when rapid therapeutic plasma levels are required (e.g. digoxin).
Clearance
Clearance (Cl) is defined as the volume of blood cleared of drug per unit time, and the units are normally litres per hour or millilitres per minute. It describes the ability of the body to remove a drug from blood either unchanged in the urine, gut or sweat, or after metabolic conversion. It is not an indicator of how much drug is being removed but the theoretical volume of blood or plasma that is completely cleared of drug in a given time. Clearance is important because it helps to determine the maintenance dose of a drug to achieve the desired plasma concentration.
Half-life is important because it determines both the time to reach steady-state conditions with chronic dosing and the time for elimination. As a rule of thumb, it takes approximately 3 – 5 half-lives to achieve steady-state conditions. Drug elimination is the mirror image: it normally takes 3 – 5 half-lives for a drug to be eliminated from the plasma. Half-life also helps to determine the frequency of dosing.
Half-life is proportional to Vd and inversely proportional to clearance:
The larger the Vd, the more the drug is concentrated in the tissues and not in the blood. It is only the drug in the blood that is exposed to clearance by the liver or the kidneys. Therefore increasing Vd increases half-life. A decrease in the efficiency of elimination (i.e. the clearance) will obviously increase the half-life as well.
Half-life
This is a particularly important concept. It is the time taken for the amount of drug in the body (or the plasma concentration) to fall by half. The elimination of a drug is usually an exponential process meaning that a constant proportion of the drug is eliminated per unit time. |
Courtesy of Simon Wills
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Half-life is important because it determines both the time to reach steady-state conditions with chronic dosing and the time for elimination. As a rule of thumb, it takes approximately 3 – 5 half-lives to achieve steady-state conditions. Drug elimination is the mirror image: it normally takes 3 – 5 half-lives for a drug to be eliminated from the plasma. Half-life also helps to determine the frequency of dosing.
Half-life is proportional to Vd and inversely proportional to clearance:
Half-life (hrs) = 0.693 x Volume of distribution (L) ÷ Clearance (L/hr)
The larger the Vd, the more the drug is concentrated in the tissues and not in the blood. It is only the drug in the blood that is exposed to clearance by the liver or the kidneys. Therefore increasing Vd increases half-life. A decrease in the efficiency of elimination (i.e. the clearance) will obviously increase the half-life as well.