Lecture 53 – Drug absorption, distribution and elimination Flashcards
bioavailability
the quantity of drug reaching the systemic circulation/quantity of drug administered
issues with bioavailability
o failure to be absorbed
destruction within the GIT
stomach acid, enzymes
enzymes in the intestinal wall
insolubility
destructions before reaching systemic circulation
hepatic first-pass elimination
bioavailability 10%?
Just multiple dose by 10, the necessary dose increases as bioavailability decreases
Volume of distribution, Vd
The volume which would have to hold the amount of drug in the body for it to be at a concentration equal to the plasma drug concentration
Vd is influenced by
o Protein binding
o Access to body compartments
o Lipid solubility
clearance
o = metabolism + excretion/ [drug] plasma
o Imagine a drug that is 100% cleared in a single pass through the kidney. Its clearance will be equal to the renal blood flow rate.
Clearance is mostly influenced by
o Most of the drug clearance happens from the blood
o Liver function
o Renal function
Half-life t1/2
o The time taken for C plasma to fall by half
Half-life is affected by
o Clearance
o Volume of distribution
o T ½ = 0.693 x Vd / clearance
Principles of pharmacokinetics
o ADME
o Absorption, distribution, metabolism, excretion
absorption
o All routes of drug delivery require absorption across barriers, except injection into the blood
Methods of drug administration
o Intravenous = fastest, always 100% bioavailability
o Intramuscular = Faster than oral, usually 100% bioavailability
o Oral = slowest, subject to elimination on the way thus possible low bioavailability
Absorption and Fick’s law
o Absorption usually follows Fick’s law
o Thus for rapid absorption:
Large SA
Increase C1 = larger dose
Decrease C2 = high blood flow
Thin barrier
Lipid-solubility, small size
Absorption after oral administration
- Absorption after oral administration
villi
o Are capillarioricious
o Solutes are washed away as they are absorbed: C1-C2 maximised so absorption rate is maximised
o Villi on villi = huge SA for absorption
Mechanisms of absorption from the gut
o Lipid diffusion = passive
o Aqueous diffusion = through aqueous pores
o Carrier transport = facilitated diffusion/active transport
distribution
o Blood goes to most tissues
o Again related to Fick’s law of diffusion
The basics of distribution (mostly happens at capillaries)
o Higher free concentration in than out = drug diffuses out
o Higher free concentration out than in = drug diffuses in
o Also there are specific transporters for some drugs
Barriers to permeation: cell membranes
Membrane area»_space; area of pores: lipid soluble drugs permeate much more rapidly than water-soluble drugs
Brain capillaries are ‘tight’
Tight junction between brain capillary endothelial cells prevents pericellular passage
Blood-brain barrier
o Capillaries in the brain are ‘tight’ and have active export transport systems
o To get from the blood to the brain, a drug has to cross the endothelium transcellularly
Active transport/lipid diffusion
Capillary structure and drug distribution
o Organs with fenestrated capillaries (kidneys, intestines, liver) are readily accessible to all drugs
o Organs with diffusionally-tight capillaries (brain, testes) are accessible mainly to lipid-soluble drugs
o Other organs have intermediate accessibility
Drugs binding to proteins (basics)
o Equilibrium process
o Albumin is a general binding protein, but specific proteins exist for several hormones (e.g. thyroxin binding globulin)
Thyroxine (T4)
o 99.96% protein bound in the plasma (mostly to thyroxine binding globulin)
o Volume is distribution about 10L
o Half-life about 7 days
Binding of protein to drugs
o Effect of the binding depends on affinity and amount of protein relative to drug
o If the protein is in the blood, then
Volume of distribution is decreased
Renal filtration is decreased
o If the protein is outside the blood
Volume of distribution is increased
o Half-life is typically increased (either way)
Metabolism
Many cells can metabolise some drugs, but the vast majority of drug metabolism is in the liver
First-pass metabolism
Hepatic first-pass metabolism = venous drainage of the GIT goes to the liver
Hepatic metabolism of drugs
o Inactivates drugs
o Activates drugs (prodrugs)
o Makes drugs more easily excreted by the kidneys
o 2 main phases
Hepatic metabolism of drugs: phase I
o Modification of functional groups
o Mostly by cytochrome P450 enzymes (CYP)
Hepatic metabolism of drugs: Phase II
o Attachment of a sugar derivative (conjugation)
o Enhances water solubility
Enzymatic reactions are saturable
V = reaction velocity = Vmax x [substrate]/Km + [substrate]
Excretion
o The kidneys are specialised organs of excretion
o They convert red liquid (blood) into yellow liquid (urine) of variable intensity
The nephron/renal mechanisms
Filtration, secretion, reabsorption
Filtration
o About 180L per day
o Physical separation on the basis of size and charge
o Driven by blood pressure
o Non-saturable
o Small solutes only, proteins excluded
secretion
o Active pumping of solutes into the filtrate
o Competition between substrates can occur
o Specific classes of molecules
o Saturable
reabsorption
o Active processes/pumping (as for secretion)
o Passive diffusion (lipid soluble molecules, non-saturable)
Forced alkaline diuresis in aspirin overdose
o Maximises filtration
o Prevents reabsorption of aspirin by pH trapping the aspirin in the urine
Renal mechanisms
filtration
