Introduction to Pharmacokinetics Flashcards
What is quality use of medicines?
Selecting management options wisely
Choosing suitable medicines if a medicine is considered necessary
Using medicines safely and effectively
What is pharmacokinetics and pharmacodynamics?
Pharmacokinetics = what the body does to the drug
Pharmacodynamics = what the drug does to the body
What are the pharmacokinetic considerations?
Remember ADME
Absorption
Distribution
Metabolism
Excretion
Why focus on blood concentrations?
Easiest to measure
Difficult to measure concentration at effect site (invasive), pharmacological effect, and outcome
How and where does oral absorption take place?
Drugs can be absorbed by passive diffusion or active transpoort across the mucosa
Site of oral absorption varies:
Intestine = large surface area, rich bloody supply, pH 6.5 - 7
Stomach = smaller surface area, coated in thick mucus, highly acidic
NOTE: pKa and pH don’t necessarily predict absorption
What is gastric emptying and what does it do?
Movement of material from the stomach into the intestine
Determines time to reach intestine
Influences onset and rate of absorption
Influenced by otehr drugs and food
Importance and influence depend on dissolution-rate and permeability-rate
What is metoclopramide and propantheline and what are they used for?
Used to increase or delay gastric emptying when combined with drugs
Metclopramide = increase Propantheline = delays by slowing GI transit
What impact on GI transit time do polar drugs have?
Polar drugs are absorbed slowly due to poor intestinal permeability - GI transit may remove them from the site of absorption
They are active transporters and are transit dependent
What is an acid labile drug?
A drug that is easily destroyed in an acidic environment
Slow gastric emptying will lead to prolonged exposure to acid and drug degradation
What are barriers to systemic absorption?
Degradation in the lumen Metabolisation by CYP3A4 in enterocytes Exportation by P-glycoprotein Metabolisation in portal blood Metabolisation of excretion in the liver
What are two causes of low bioavailability?
Poor intestinal permeability
Extensive first pass hepatic elimination
What factors affect the rate and extent of drug absorption from the GI tract?
Formulation of drug characteristics such as tablet dissoltion / disintegration, influence of excipients, and stability of drug GI lumen
Pharmacokinetic characteristics of drug such as first pass effect (metabolism by bacteria, gut wall, liver etc)
Patient characteristics such as GI transit time and influence of disease
Presence of substances in GI tract such as food or drugs (co-administration slows down absorption)
What are the different routes of elimination?
Metabolic biotransformation in liver, intestine, kindeys, or lungs Renal elimination Biliary excretion Exhalation Other routes eg lactation
What is metabolic biotransformation?
Biotransformation can be oxidationn, reduction, or conjugation
Enzymatic chemical conversaion or conjugation that makes a metabolite more soluble
Generally detoxification but may be activation
What are the ofur common reactions involved in drug metabolism?
Oxidation
Reduction
Hydrolysis
Conjugation
What is clearance (CL) and what is its significance?
Measure of efficiency of drug elimination from the body used to estimate the maintenance dose rate
Calculated from volume of blood cleared of a drug per unit of time (Volume / Time eg L/h)
MOST IMPORTANT clinical pharmacokinetic parameter because it determines the average concentration achieved if a drug is administered at regular intervals
How is clearance calculated?
After a single dose: CL = F x Dose / AUC
During steady-state dosing: CL = F x Dose rate / Css
(Css = concentration at steady-rate when input rate = output rate)
Clearance is additive so if the drug has more than one route of elimination the total clearance is the sum of each individual clearance
(CL = CL renal + CL metab + CL bile etc)
What are the three processes involved in renal elimination?
Filtration (glomerulus) = all unbound drug in plasma is filtered
Secretion (proximal tubule) = Carrier mediated, drugs may interact for the same carrier
Passive reabsorption (distal tubule) = relatively insoluble and uncharged drugs undergo passive reabsorption
Therefore, renal clearance = total of all types of clearance methods
How are the characteristics of active secretion in the renal excretion process?
Transporter for anions (-ve) and cations (+ve) ions
May be saturated at higher doses
Competitive drug interactions
What are the characteristics of reabsorption in the renal excretion process?
Generally a passive reabsorption in proximal tubule
Lipophilic molecules tend to be reabsorbed
Polar molecules do not tend to be reabsorbed
What is variability in drug response?
The product of pharcokinetics and pharmacodynamics
Old age can impact varaibility as it changes clearance factors, changes pharmacokinetics
What is the clinical significance of drug interactions?
Patient characteristics Mechanism interaction Nature of pharmacodynamic response Safety margin of the interacting herb and drug Dose and duration of therapy Time course of drug interaction Order and timing of administration
What are the 4 basic pharmacokinetic parameters and what do they affect?
- Clearance (CL) = volume / time
The efficiency of drug elimination which then determines the dose rate - Volume of Distribution (V) = volume
Th extent of distribution which then determines the loading dose - Bioavailability (F)
A fraction representing the dose absorbed after an oral administration which then determines the dose adjustment between routes of administration - Half life = Time (t 1/2)
A description of how long a drug / metabolite stays in the body (interplay of V and CL) which the determines the frequency of dosing
