Drug distribution Flashcards
What is drug distribution?
Definition- Dispersion of a drug among fluids and tissues of the body
Important points:
The aim of good therapeutics is to deliver medicines to their site of action at effective concentrations
In multiple-dose therapy, the aim is to keep these levels as stable as possible
What are first-order kinetics?
Most drugs obey first-order kinetics
A constant fraction of drug is removed —-> constant clearance
The time to remove the drug is independent of dose (if you increase [dose] the same fraction is removed) —-> constant half-life
What are the zero-order kinetics?
A few drugs obey the zero-order kinetics
A constant amount of drug is removed
The bigger the dose the longer the time to remove it
What are saturation points?
Saturable processes involved in drug elimination; enzymes, transporters in the liver and kidneys
Drugs may accumulate very quickly
How does mixed kinetics happen?
First order kinetics resumes when concentration decreases below saturation point
What are the parameters of pharmacokinetics?
Pharmacokinetics parameters: Volume of distribution (Vd) Half-life (t1/2) Clearance (CL) Bioavailability (F)
What is the volume of distribution?
Total mount of drug/ [Plasma]= Apparent volume of distribution (Vd)
E.g. 20mg i.v. dose; 2mg/L drug in plasma —> V= 10L
Vascular space: 4L + Extravascular space: 6L
Indicate the extent of distribution for a drug
Clinically important for adjusting dosage
Influenced by lipid/water solubility, binding to plasma proteins
What is elimination and clearance?
Describes activity of metabolising enzyme/excretion mechanisms Plasma clearance (CL): Volume of plasma cleared of drug per time (ml min^-1) CL= Rate of elimination/ [drug plasma] A constant for 1st order reactions CL increases half life decreases CL = Dose x F / AUC CL = Vd x Ke
What is bioavailability?
F: Fraction of drug in circulation compared to dose
Measures extent of absorption
Calculated by: Equal oral/iv doses, measure AUC oral / AUC iv
e.g. oral dose, F = 0.1 (10% bioavailability)
How does one choose a delivery route of drug?
Low bioavailability is caused by: Poor absorption Chemical reactions at site of delivery First-pass metabolism Choice of route guided by: Bioavailability Chemical properties of drug Convenience Need to control specificity of action Desired onset/duration/offset of action
What happens with dosing regimens?
Multiple dosing leads to a ‘steady state’
Additional doses administered before [drug] falls to zero
[Drug] variation depends on half-life and dose interval
Multiple dose therapy compromises:
Minimisation of drug level variability
Simplicity
What are the theoretic behind the stable state?
Idea of dosing regime is to balance:
Dosing rate = rate of elimination
—> Dosing rate = clearance x Css
Dosing rate x F= CL x Target concentration
Example
A 70kg patient with asthma is to be treated with theophylline (non-selective phosphodiesterase inhibitor, causes broncho-relaxation)
Narrow therapeutic range and potentially fatal effects in overdose
Treatment aims at a ‘steady state’ level of 15 μg/ml in plasma
The clearance of the drug is 48ml/min/70kg and its half life is 8h
Treatment by intravenous bolus injection
Dosing rate x F = clearance x Css
Dosing rate x 1 = 48ml/min/70kg x 15μg/ml
-> dosing rate = 720μg/min/70kg
-> daily dose = ~1.02g for this patient (720µg x 1440 min = 1.02 g)
What are the general rules of achieving a steady state?
Repeated doses of drug eventually produce a steady state (plateau) concentration
Time to plateau is 4-5 x drug half-life
When dose is changed a new plateau is reached in 4-5 half lives
Steady state levels are not actually flat
Fluctuation size is inversely proportional to the number of daily doses
Fluctuations create the potential for sub-therapeutic treatment or toxicity
For drugs with long half lives achievement of steady state can be accelerated by a loading dose
