4. Pharmacokinetics Flashcards
what is the journey of the drug through the body?
ADME Absorption Distribution Metabolism Excretion
what are the major routes by which drugs may be administered?
dermal intramuscular subcutaneous intraperitoneal intravenous inhalation ingestion
what 2 categories do the actions of drugs fall into?
systemic - entire organism
local - restricted to one area of the organism
what are the general terms for the routes of administration and what do they mean?
enteral - gastro-intestinal admin
parenteral - outside GI tract
what are the enteral routes of drug administration?
sublingual, buccal, oral, rectal
what are the parenteral routes of drug administration?
intravenous, intramuscular, subcutaneous, percutaneous, inhalation
in what 2 ways do drug molecules move around the body?
- bulk flow transfer (in the bloodstream)
2. diffusional transfer (molecule by molecule over short distances)
what is the route of absorption of a drug?
drug goes to the GI tract -> absorbed -> travels to the liver via the hepatic portal system -> enters systemic circulation
what are the main barriers to drug movement?
cell membranes
how can drugs cross barriers?
- diffusing through lipid
- diffusing through aqueous pores in the lipid (if they are polar)
- carrier molecules
- pinocytosis
what does the degree of ionisation of a drug depend on?
- the pKa of the molecule
- the pH of the medium (ionised = more water soluble, non-ionised = more lipid soluble)
how does pH suppress or activate the ionisation of aspirin?
aspirin is acidic (pKa ≈ 3.4) so when it enters the stomach (pH 1) it is non-ionised. as it exists mainly in its non-ionised form in the stomach it can readily diffuse across the lipid bilayer. the pH in the small intestine is more basic so aspirin becomes ionised and cannot travel through the membrane and there is slower absorption.
what factors influence drug distribution?
- regional blood flow
- extracellular binding (plasma-protein binding)
- capillary permeability
- localisation in tissues
how does regional blood flow influence drug distribution?
tissues that are well perfused are likely to be exposed to a higher concentration of the drug
some tissues may increase in perfusion when their activity increases (e.g. skeletal muscle during exercise)
highly metabolically active tissues tend to have a greater blood flow and denser network of capillaries
how does extracellular binding (plasma-protein binding) influence drug distribution?
50-80% of acidic drugs bind to plasma proteins
albumin can bind both ionised and non-ionised drugs
how does capillary permeability influence drug distribution?
distribution depends heavily on capillary architecture:
- fenestrated: more permeable to drugs
- continuous: found in normal vessels, has water-filled gap junctions
- discontinuous: large gaps between endothelial cells
how does localisation in tissues influence drug distribution?
fat isn’t usually highly perfused so it is a very lipophilic environment and so drugs that are lipophilic tend to localise in fatty tissue
what are the 2 major routes of drug excretion?
- kidney - responsible for elimination of most drugs
2. liver - some drugs are concentrated in the bile
which sections of the kidneys have a role in drug excretion? describe their role
- glomerulus - drug-protein complexes are not filtered
- proximal tubule - active secretion of acids and bases
- proximal and distal tubules - lipid soluble drugs reabsorbed
how does the majority of a drug get into the urine?
via active secretion rather than ultrafiltration
where are xenobiotics mostly secreted?
the kidneys
why might treatment with IV sodium bicarbonate increase aspirin excretion?
sodium bicarbonate increases urine pH -> increased pH ionised the aspirin -> aspirin becomes less lipid soluble -> less reabsorbed from tubule -> increased rate of excretion
how are drugs excreted by the liver?
some drugs are concentrated in bile and bile is secreted into intestines
other than the kidneys and liver, what other routes of excretion are there?
- lungs
- skin
- GI secretions
- saliva
- sweat
- milk
- genital secretions
what does biliary excretion allow?
the concentration of large molecular weight molecules that are very lipophilic
describe the active transport systems that secrete drugs into bile
the transport systems transport bile acids and glucoronides into bile - drugs can “hitch a ride” on these systems because they are non-polar
what can enterohepatic cycling lead to and how?
drug persistence
the drug/metabolite gets excreted into the gut but then is reabsorbed and returned to the liver via the enterohepatic circulation
define ‘bioavailability’
proportion of the administered drug that is available within the body to exert its pharmacological effect
define ‘apparent volume of distribution’
the volume in which a drug appears to be distributed
define ‘biological half-life’
time taken for the concentration of drug (in blood/plasma) to fall to half its original value
define ‘clearance’
blood (plasma) clearance is the volume of blood (plasma) cleared of a drug in a unit time
how does 1st order kinetics describe the rate of elimination of a drug?
the amount of a drug decreases at a rate that is proportional to the concentration of the drug remaining in the body
what is C0?
concentration of a drug at time 0 - cannot be measured, must be extrapolated
how do you calculate volume of distribution(Vd)?
Vd = dose/C0
what is clearance (Cl) proportional to?
drug concentration in plasma/serum
how do you calculate half life (T1/2)?
T(1/2) = (Vd x 0.7)/Cl
how does zero order kinetics describe the rate of elimination of a drug?
a constant amount of drug is removed per unit time
how does zero order kinetics work? give an example of a drug that is eliminated via zero order kinetics
e.g. alcohol
something is going on that is saturating the system (usually an enzyme e.g. alcohol dehydrogenase) and once saturated the rate of removal of the drug peaks and remains constant
