L9 - Pharmacokinetics Flashcards
3 factors influencing drug targets
Mechanism of action and effects on cellular proteins
Physicochemical properties
Concentration
Concentration depends on
Absorption
Distribution
Metabolism
Excretion
Physicochemical properties
Affinity
Efficacy
Potency
Drug absorption has to cross various barriers via
Simple diffusion (dissolves into the lipid bilayer)
Aquaporins (drug needs to be small and dissolved in water)
Transporter protein
Pinocytosis (cell engulfs ECF which contains drug)
Most drugs are transported through?
Distributed by the cardiovascular system through the bloodstream
Movement of drugs usually involves penetration of?
Lipid diffusion barriers
This determines where and for how long a drug will be present in the body after administration
Physicochemical properties of drugs determined their ability to diffuse through lipids - lipid solubility
Partition coefficient
High coefficient means drug is efficient in entering lipid compartment
Non-polar drugs (needed so drugs can enter the CNS)
Physicochemical properties of drugs determined their ability to diffuse through lipids - diffusivity
Diffusion coefficient
Describes how rapidly the drug moves
Proportional to the molecular weight of the drug
Drugs with high molecular weight have slower diffusivity
Non-polar molecule diffusivity
Dissolve freely in lipids and penetrate cell membranes freely
- Increased rate of absorption from gut
- Increased penetration into brain and other tissues
- Increased renal elimination
Factors influencing drug absorption
Route of administration Molecular weight Lipid solubility pH and ionisation Carrier mediated transport
Route of administration - intravenous
By passes the gut, drug diffused straight into the blood supply
Fastest and most reliable way to control drug concentration in the plasma
Requires specialist knowledge
Route of administration - intramuscular
By passes the gut
Has to bypass muscle barriers so slower rate of delivery
Useful for drugs with a high probability of getting metabolised in the gut
E.g. insulin
Route of administration - intrathecal
Drug injected straight into the cerebrospinal fluid
Useful for drugs who need to act within the CNS and need precise concentration
E.g. local anaesthetic
Route of administration - oral or rectal
Simplest and easiest route
Drug first encounters the gastrointestinal system
Impacted by the pH and enzymes found here
Most of the absorption occurs in the ileum of the small intestine – high surface area
Additional perfusion system – portal blood system
- Will deliver the drug directly to the liver
- Is important as it is where most drugs are metabolised
Route of administration - percutaneous
Skin patches used to absorb drug straight through the skin
However, hard as the skin is typically impermeable
- Drug needs to be very non-polar
- Typically hormonal drugs
Route of administration - inhalation
Restricted to 2 classes of drugs
- Those acting only in the lung – asthma
- General anaesthetic
Molecular weight
Affects rate of diffusion
Lipid solubility
Ability to cross lipid membrane by diffusion
pH and ionisation
Many drugs are weak acids or bases
Weak acid = HA H+ + A-
Uncharged drug can cross lipids (undissociated form)
Charged drug cannot cross lipids (dissociated form)
At low pH (acid environment)
- Equation pushed left – drug in undissociated form
Carrier mediated transport
Polar molecules (sugars, amino acids, metal ions) dependent upon saturation and competitive inhibition
Aspirin as an example of the effect of pH
In the stomach – pH of 3
- Most of drug in its undissociated form
- Rapid diffusion across lipid barriers
In the plasma – pH of 7
- Less of drug in undissociated form
- Concentration of drug will rise relative to the acidic compartment
- Trapped because it is dissociated and cannot diffuse
In the urine – pH of 8
- Most of the drug is in its dissociated form
- Drug becomes increasingly trapped
pKa
= pH + log10(HA/A-)
Aspirins pKa
Weak acid - pKA of 3.5
Weak acids become trapped in?
Basic compartments
E.g. renal tubules
Urinary acidification causes?
It slows excretion of weak acids
Increasing plasma pH (sodium bicarbonate) causes weak acid drugs to be extracted from CNS back into plasma where they get trapped
- Decreased neurotoxicity
- E.g. following poisoning with aspirin
