S10-11) Pharmacokinetics Flashcards
Distinguish between pharmacodynamics and pharmacokinetics
- Pharmacokinetics – what the body does to the drugs
- Pharmacodynamics – what the drugs do to the body
What are the four main processes in pharmacokinetics?
- Drug in:
I. Absorption
II. Distribution
- Drug out:
I. Metabolism
II. Elimination
What are the two forms of drug administration?
- Enteral – delivery into internal environment of body (GI tract)
- Paraenteral – delivery via all other routes that are not the GI
Identify the different types of drug administration
- Paraenteral: intrathecal, intramuscular, transdermal, inhalation, intravenous, subcutaneous
- Enteral: rectal, oral, sublingual
Mnemonic: OI, IT IS SIR
How are drugs absorbed?
Drug mixes with chyme, then enters small intestine where most absorption occurs
Which processes facilitate drug absorption?
- Passive diffusion
- Facilitated diffusion
- Primary / secondary active transport
- Pinocytosis
Describe drug absorption through passive diffusion
Lipophilic drugs (weak acids/bases) diffuse passively into GI capillaries
Describe drug absorption through facilitated diffusion
- Molecules with net ionic charge can be carried across GI epithelia
- Passive process based on electrochemical gradients
- Solute carrier transporters are either OATs(-) and OCTs(+) which are highly expressed in GI, Hepatic and Renal Epithelia
Describe drug absorption through secondary active transport
- SLCs facilitate this process (no ATP)
- Transport driven by pre-existing electrochemical gradient across GI epithelial membrane
What are the physicochemical factors affecting drug absorption?
- Surface area
- Drug lipophilicity and pKa
- Density of SLC expression in GI
What are the physiological factors affecting drug absorption?
- Blood Flow: increases after a meal
- GI Motility: decreases after a meal
- Food/pH
What are the factors affecting drug absorption in terms of First Pass Metabolism by GI and Liver?
- Gut Lumen: enzymes can denature drugs
- Gut Wall/Liver: some drugs are metabolised by cytochrome P450s (phase I & phase II enzymes)
What is bioavailability?
Bioavailability is the fraction of a defined dose which reaches its way into a specific body compartment
What is the most common means of calculating bioavailability?
- CVS (circulation) is most common reference compartment
- Most common comparison is (O)/(IV)
How does one calculate oral bioavailability?
It is the amount of drug administered (AUC) via the oral route divided by the AUC via the IV route
I.e AUCO/AUCIV
Why do drugs distribute?
To reach and interact with therapeutic and non-therapeutic target
Outline the processes involved in the first stage of drug distribution
- Bulk flow – large distance via arteries → capillaries
- Diffusion – capillaries → interstitial fluid → cell membranes → targets
What are the major factors affecting drug distribution?
- Drug molecule hydrophilicity
I. Lipophilic drugs freely move across cell membrane
II. Hydrophilic drugs dependent on electrochemical gradients
- Drug binding to plasma and/or tissue proteins e.g. albumin, lipoproteins, glycoproteins
Describe drug binding to plasma and/or tissue proteins
- Only free drug molecule can bind to target site(s)
- Binding in plasma/tissue decreases free drug available for binding
- Binding forces not strong (bound/unbound in equilibrium)
What are the three main body fluid compartments?
How can one calculate volume of distribution?
Vd = Drug dose/ [Plasma Drug]t=0
What assumptions are made when calculating Vd?
- Pretends that drug fully distributes throughout the body at time zero
- Groups all fluid compartments into one compartment
- Referenced to [plasma] (easiest to measure)
What do smaller and larger Vd values indicate?
- Smaller Vd values: lesser penetration of interstitial/intracellular fluid compartment
- Larger Vd values: greater penetration of interstitial/intracellular fluid compartment
Which units are used to measure apparent volume distribution?
- Litres (assume ‘standard’ 70 kg body weight)
- Litres/kg (more referenced to individual patient body weight)
What are the factors affecting Vd?
- Changes in regional blood flow
- Pregnancy
- Paediatrics/neonates/pre-term
- Geriatrics
- Cancer patients
Describe the features of hepatic drug metablism
- Drug metabolism occurs in liver via Phase 1 and II enzymes
- Enzymes are expressed throughout body tissues
Describe the action of Phase I and II enzymes
- Metabolise (& inactivate) drugs
- Increase ionic charge to enhance renal elimination
How is Phase 1 Metabolism carried out by cytochrome P450 enzymes?
- Phase 1 enzymes (CYP450s) catalyse redox; dealkylation; hydroxylation reactions
- CYP450s are generalists – metabolise very wide range of molecules
What are the properties and actions of metabolised drugs after Phase I metabolism?
- Metabolised drugs have increased ionic charge
- Metabolised drug eliminated directly or go onto Phase II
How is Phase II Metabolism is carried out by hepatic enzymes?
- Phase II enzymes (cytosolic enzymes) exhibit more rapid kinetics than CYP450s
- Phase II metabolised drugs further increase ionic charge & enhance renal elimination
What are the factors affecting drug metabolism?
- Age
- Sex e.g. alcohol metabolism slower in women
- General health/dietary/disease (hepatic, renal, CVS)
Identify the main routes of drug elimination
- Main route of drug elimination is kidney
- Other routes: bile; lung; breast milk (deliver to baby); sweat, tears; genital secretions; saliva
What processes are involved in renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
Briefly describe glomerular filtration
Unbound drug enters glomerulus via Bowman’s capsule for filtration
Briefly describe proximal tubular secretion
- Water reabsorbed along tube length
- Lipophilic drugs diffuse out renal tubules back into plasma
What is clearance?
Clearance is defined as the volume of plasma that is completely cleared of the drug per unit time (measured in ml/min or ml.min-1)
Why is clearance better thought of as ‘Apparent Rate of Elimination’?
Renal volume of plasma cannot be ‘completely’ cleared of drug via glomerular filtration/ tubular secretion
What is Drug Half Life (t1/2)?
Drug half life is the amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it had when it was first measured
Explain the relationship between drug half life, volume of distribution and clearance
- t1/2 is dependent on Vd and CL
- If CL stays same and Vd increases then t1/2 also increases
- If CL increases and Vd stays the same then t1/2 decreases
Explain the principles of linear elimination kinetics
The rate of metabolism / excretion is proportional to [drug] per unit time
What are the features of linear elimination kinetics?
- Plenty of Phase I/II enzyme sites
- Plenty of OAT/OCT transporters
What happens when elimination processes become saturated?
- Saturated processes = rate limited
- In elimination kinetics, this is referred to as saturated / zero order
Outline the features of zero order kinetics
- Drugs at/near therapeutic dose with saturation kinetics
- Fixed rate of elimination per unit time
- Relatively small dose changes can produce large increments in plasma [drug]
