Clinical Pharmacology Terms Flashcards
What is pharmacokinetics?
This is what the body does to the drug, and can be reduced to 4 main processes - ADME Absorption Distribution Metabolism Excretion/ elimination
What affects drug absorption?
Extent of absorption depends on the drug formulation and the site or route of administration.
Small bowel absorbs most orally administered drugs; the controlling rate is therefore primarily gastric emptying.
What is first pass metabolism?
Drugs given orally with a high clearance are absorbed from the GIT into the portal circulation.
Here they travel to the liver and are metabolised. This will reduce the circulating plasma concentration of the drug.
In cirrhosis, the liver is bypassed due to portosystemic anastomoses, and systemic levels of drugs increase tenfold.
What determines drug distribution?
This depends on the apparent volume of distribution (Vd)
Vd = Dose/ Plasma drug concentration
This is the theoretical volume occupied by the total amount of drug in the body relative to its plasma concentration.
Water-soluble (polar) drugs that distribute through the aqueous compartments have relatively low volumes of distribution and high plasma concentrations.
Drugs that are highly lipid-soluble will have apparent large volumes of distribution but a relatively low plasma concentration
What are the properties of drugs with a low, medium and high Vd?
Low Vd - confined to the intravascular compartment, large/charged molecules; plasma protein-bound
Medium Vd - ECF compartment; small hydrophilic molecules
High Vd - all body compartments including fat; small lipophilic molecules especially if bound to tissue protein
What is clearance?
This is the volume of plasma cleared of a drug per unit time. Clearance can be impaired with defects in hepatic, cardiac, or renal function.
CL = Rate of elimination of a drug/ plasma drug concentration
What is bioavailability?
Fraction of administered drug reaching systemic circulation unchanged.
For an IV dose, F = 100%.
For an oral dose, F = <100% due to incomplete absorption and first-pass metabolism
What are first-order pharmacokinetics?
These terms are related to clearance.
Clearance may be a first-order process (a constant fraction is eliminated per unit time). For example, 20% of the drug may be eliminated every 2 hours. Elimination of the drug from the body under first-order elimination is characterised by a constant half-life throughout elimination.
A semi-logarithmic graph will therefore be linear.
This accounts for almost all drugs.
This is sometimes referred to as flow-dependent elimination.
How is a steady-state achieved for first-order pharmacokinetics?
This is achieved when the rate of intake of the drug matches its elimination from the body.
For drugs with first-order pharmacokinetics, the accumulation of the drug can be predicted because it is also a linear process. 90% of the steady-state levels will be reached between 3 and 4 half-lives.
What are zero order pharmacokinetics?
Drugs with zero-order pharmacokinetics have different rates of elimination at different drug levels in the body.
A constant amount is eliminated per unit time. For example, 10mg per hour is eliminated so that if there’s drug toxicity the time for clearance will increase with the higher blood level.
Clearance tends to increase at lower levels of the drug.
Which clinically important drugs have zero-order pharmacokinetics?
Phenytoin
Theophylline
Salicylates
Ethanol
The clinical importance of dose-dependent elimination is that small increases in the drug dose may lead to large increases in the amount of available drug.
What is a drugs half life?
T1/2 (elimination half life) is the time in hours necessary to reduce the drug concentration in serum to one half.
Half-life can be prolonged by either low clearance and/or a high volume of distribution. If the half-life extension is due to increased volume of distribution then there will be no accumulation of the drug. If there is low clearance causing the prolonged half-life, the drug will tend to accumulate.
What is a loading dose?
Drugs with a long half-life need to be given at a higher dose, to begin with, to achieve a steady state in the plasma more quickly.
Loading dose = target level x Vd/ bioavailability
A loading dose is only chosen if a condition needs treatment quickly and the time to acquire a steady state is long (i.e. long half life).
In renal and liver disease, the loading dose usually stays the same, but the maintenance decreases.
How can the elimination fo weak acids be enhanced?
Ionised species are trapped in urine and cleared quickly. Neutral forms which are lipophilic can be reabsorbed.
Weak acids include phenobarbitol, methotrexate, aspirin. These are trapped in basic environments. Treat an overdose with bicarbonate to alkalinize the urine.
What reactions occur in phase I metabolism?
Most drugs are metabolised in the liver. Phase I reactions include: - reduction - oxidation - hydrolysis
These involve cytochrome P450 isoforms.
Yield slightly polar, water soluble metabolites that are usually still active.
Older patients lose phase I reactions first.
