PK: Movement Across Cell Barriers & Ion Trapping Flashcards
4 principles of pharmacokinetics
ADME
- Absorption
- Distribution
- Metabolism
- Excretion
What does endocytosis apply to
Large molecules
Drugs get engulfed
Formula for bioavailability
What does distribution depend on (5)
- Lipophilicity - a lipophilic drug will be distributed easier
- Blood flow e.g. brain vs skin
- Capillary permeability
- Plasma and tissue binding (albumin slows the process)
- Volume of distribution
Formula for Volume of Distribution
Principle of first order kinetics
Rate of elimination is proportional to the [drug] conc in the body
Zero order kinetics principle
Give an example
Amount of drug eliminated is independent of drug conc in the body
ie rate of elimination is constant
e.g. aspirin
Define steady state
Rate of administration = rate of elimination
What is the most important route of elimination
What challenge faces this route of elimination and how is it overcome
Kidney
Cannot get rid of lipid soluble drugs as they are passively reabsorbed
- Liver turns lipophilic drugs into water-soluble substances that are easily removed by kidneys
- 2 metabolic rxns do this In liver
Name the 6 INDUCERS of phase I of excretion in the liver
PCRABS
- Phenytoin
- Carbamazepine
- Rifampin
- Alcohol - chronic
- Barbituates
- St John’s Wort
Name the 7 inhibitors of phase I of elimination in the liver
GPACMAN
- Grapefruit
- Protease inhibitors
- Azole anti-fungals
- Cimetidine
- Macrolides (except azithomycin)
- Amiodarone
- Non-DHP CCBs (dialtiazem and verapamil)
Overview of the 2 compartment model
What is one of the first barriers an oral medication must overcome
Epithelial lining of the GIT
What is the major barrier to drug transport
The hydrophobic core of a biological membrane
What are the compartments a drug can move through
What effect does the acidic environment of the stomach have on the ionised state of a drug
- Acidic drugs remain unionised in the stomach due to the acidic environment of the stomach
- Basic drugs cannot be absorbed so they pass into pyloric sphincter into SI and are absorbed there
Define first pass metabolism
Drugs travel to the liver via the portal system, where they are immediately metabolised
Define enterohepatic cycling
Some drugs are secreted back into the SI via bile
Why might not all the drug dose be absorbed
Molecules may bind to intestinal content, so they cannot pass through mucosal cells
While other may be broken down by bacterium in ileum and colon
oral dose vs IV dose
How does an oral drug get to site of action
- Must cross the epithelial cell barrier that lines the GIT, and is then ABSORBED into blood
- Then carried by blood to tissues (BULK FLOW) - crosses endothelial cell barrier from blood to tissue (DISTRIBUTION)
Influence of chemical nature of drug on bulk flow
Irrelevant
Influence of chemical nature of drug on diffusion
Diffusion depends on the drug
Where is the epithelial barrier present
What does it consist of
At GI mucosa and renal tubule
Consists of cells tightly connected to each other
What do CNS and placenta contain
An impermeable layer of periendothelial cells (pericytes)
Name the 4 main ways a drug crosses the membrane
- By diffusing directly through lipid (main way)
- By combination with a transmembrane carrier protein that binds a molecule on 1 side of the membrane then changes conformation and releases it on the other
- By diffusing through aqueous pores formed by special proteins (aquaporins) that traverse the lipid
- By pinocytosis (trapping within the cell of a small vesicle containing EC constituents e.g. insulin at BBB)
Define Fick’s Law
Rate of diffusion depends on the conc gradient of the drug across the membrane and on the thickness, area and permeability of the membrane
What is diffusion directly through the lipid membrane dependent on
Conc of drug
Oil/water partition coefficient
Conc of protons
SA of absorbing membrane
** not saturable and low structural specificity
Facilitated diffusion
Passive in the direction of its electrochemical gradient
Where is the active transport mechanism (with the carrier protein) important
- BBB
- GIT: 5-fluorouracil
- Renal tubule: penicillin
- Biliary tract
- Placenta
What AA enters the brain by means of facilitated diffusion
L-dopa
Unsaturable vs saturable process
What is diffusion proportional to
The square root of MW
What is the MW of most drugs
200-2000 Da
How is lipid solubility measured
By the oil:water partition coefficient
i.e. how avidly a drug dissolves in lipid compared to how avidly it dissolves in water
Drugs with a high oil:water partition coefficient will be lipophilic and be able to readily traverse membranes
Define ion trapping
What sort of substances does it occur with
Occurs when a drug, in its ionised state, gets trapped on 1 side of a membrane that divides 2 compartments with different pH values
Occurs with weak acids and weak bases (exist in both ionised and unionised form)
In either case the ionised form has very low lipid solubility and is virtually unable to permeate membranes except where a specific transport mechanism exists - % depends on pH of solution
What would happen to weak acids in an acidic solution
They will not lose their proton in an acidic solution and therefore not become charged/ionised
What will happen to weak bases in a basic solution
Will not gain a proton in a basic solution and therefore will not become charged/ionised
HH equation for a weak base
HH equation for a weak acid
pKa = -log(H+ dissociation constant)
What does it mean when pH = pKa
The conc of ionised is the same as the conc of unionised
Example of application of HH equation
What effect does ion trapping have on pH partition
Ionisation affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments
Ratio is governed by pH and pKa (HH)
What effect does ion trapping have on the drug at equilibrium
The total (ionised and unionised) concentration of the drug will be different in the 2 compartments, with an acidic drug being concentrated in the compartment with high pH (ion trapping) and vice versa
pKa values of different drugs
What happens when we alkalinise the urine
We can increase ionisation of acidic substances in the renal tubule and thereby prevent their tubular reabsorption
IV Na+ bicarbonate infusion will increase plasma pH, increase urine pH and therefore increase salicylate excretion
What sort of molecules can diffuse passively across the cell membrane
Small non-polar molecules
How do some drugs (e.g. levodopa and valproate) traverse the BBB
Via transporters, which either facilitate entry into the brain or diminish it by pumping the compound from the endothelial cell interior back into the bloodstream
How does active extrusion of drugs from the brain occur
Via P-glycoprotein, an ATP-driven drug efflux transporter, and related transporter proteins
What happens to CNS-acting drugs in the brain
Actively extruded from the brain
e.g. certain opioid, anti-depressant, anti-psychotic and anti-epileptic drugs
Overview of transport of molecules
What drugs can cross the placental barrier
Drugs with a MW of < 600
- teratogens
