Drug absorption Flashcards
What does pharmacokinetics refer to?
What the body does to the drugs administered
What does ADME stand for?
Absorption- process by which unchanged drug enters the circulation
Distribution- dispersion of a drug among fluids and tissues of the body
Metabolism- transformation of a drug into daughter compound(s)
Excretion- removal of drugs/metabolites from the body
Drug elimination is both metabolism and excretion
What kinds of things would the British National Formulary contain? (Use paracetamol as an example)
Contains the basic information of drugs
E.g. Paracetamol
Indications: mild to moderate, pyrexia
Cautions: e.g. hepatic impairment (dose-related toxicity- avoid large doses); interactions (alcohol)
Dose: by month, 0.5-1 g every 4-6 hours to a max of 4 g daily; by intravenous infusion, over 15 min, 1 g every 4-6 hours, max 4 g daily, max 60 mg/kg daily
Side effects: rare but include skin reactions
What are drug in circulation determined by?
Determined by supply rate, distribution and removal from the body
For drug at site(s) of action
For metabolism and excretion from the body
What is drug absorption?
Definition- The process by which unchanged drug gets from site of delivery to the circulation
Important points:
Medicines need to be absorbed unless given directly into the circulation
Different routes of administration present different barriers to absorption
Different routes of administration result in different bioavailability and onset
Choice of delivery route is a compromise:
Speed of onset
Convenience- oral or IV?
Bioavailability- proportion of administered drug reaching the systemic circulation- 100% for drugs given IV
Side effects/specificity of action
What are the different ways drugs are absorbed?
Absorption requires drugs to cross biological barriers (layers of cells with semi-permeable, lipophilic membrane)
Most absorption occurs through cells (transcellular), some occurs between cells (paracellular)
What are the different ways through which absorption can occur?
Absorption can occur by:
Active transport through cells (very few medicines)
Facilitated diffusion through cells (few medicines)
Passive diffusion (most medicines)
What is Fick’s Law?
Rate of diffusion= surface area x concentration difference x permeability
Lipid solubility/ionisation are key determinants of permeability
What does the extent of ionisation depend on?
Most drugs are weak acids or bases and thus are ionisable
Extent of ionisation depends on:
pH of the environment
Acid/base dissociation constant of the drug
What problem do ionisable drugs present?
To diffuse across cell membranes medicines must be uncharged
Non-ionisable, lipophilic drugs are absorbed most effectively
Ionised (charged) drugs are absorbed least effectively
What are the Henderson-Hasselbalch equations?
Henderson-Hasselbalch equations predict extent of ionisation
Acidic drugs: the more unionised the drug will be as pH becomes more acidic
Basic drugs: the more unionised the drug will be as the pH becomes more alkaline
For acids: pH = pKa - log [non-ionised] / [ionised]
For bases: pH = pKa + log [non-ionised] / [ionised]
pH = pKa when drug is 50% ionized
EXAMPLE
Absorption of aspirin at the gastric mucosa
Aspirin is weak acid (acetylsalicylic acid)
Hasp Asp- + H+
pKa= 3.5
For acids: pH= pKa - log [non-ionised]/[ionised]
What is ion trapping?
Acidic drugs are absorbed efficiently from the stomach
Basic drugs are absorbed less efficiently
Note that the same principles apply to the renal excretion of drugs (alkaline urine traps and enhances excretion of acidic drugs)
Can basic drugs be given orally/
Yes- unless very basic or permanently ionised
Basic drugs absorbed poorly from stomach (pH 1-2, 1m^2)
But are absorbed better from the intestine (pH 6.6-7.5)
Surface are of intestine (100 m^2) compensates for low absorption deficiency
Many drugs are absorbed in the intestines
What are the Lipinksi rules?
A rule based approach to ADME optimisation?
An orally-active drug likely has no more than one violation of the following:
Molecular weight < 500 da
No more than 5 H-bond donors
No more than 10 H-bond acceptors
Log P <5 9partition coefficient)
(The rules don’t predict pharmacological activities, ADME optimisation might minimise desirable properties (H bonding) for receptor binding
