4. Pharmacokinetics Flashcards
What are the 4 (6) parts of the journey of a drug through the body?
(• Administration) • Absorption • Distribution • Metabolism • Excretion (• Voided)
What is the difference between systemic and local administration?
- Systemic - entire organism exposed to drug
* Local - one area exposed to drug
What is the difference between enteral and parenteral administration?
- Enteral - via GI tract e.g. sublingual, buccal, oral, rectal (easier)
- Parenteral - everything apart from GI tract e.g. IV, inhalation etc. (more skill required)
How does the ionisation of drugs (most of which are weak acids or bases) effect their solubility?
- Ionised - more water soluble
* Non-ionised - more lipid soluble
What mechanisms the can transfer of molecules across membranes occur by?
- Passive diffusion (most common)
- Facilitated diffusion
- Active transport
- Pinocytosis
- Filtration (small water soluble molecules)
- Paracellular transport
In what 2 ways do drug molecules move around the body?
- Bulk Flow Transfer - move in bulk through the bloodstream to the tissues
- Diffusion Transfer - molecule by molecule over short distances
How do lipid and aqueous (polar/ionised) molecules cross lipid barriers?
- Lipid molecules diffuse through lipid barriers
- Polar molecules diffuse through aqueous pores in the lipid barrier
- Carrier molecules and pinocytosis can also be used
What does the ratio of ionised to non-ionised drug molecules depend on?
- pH of environment
* pKa of molecules
Use the behaviour of aspirin to describe the pH Partition Hypothesis
- Aspirin is acidic - has pKa of 3.4
- Stomach has pH 1 - less than pKa of aspirin
- Therefore aspiring is non-ionised in stomach - can diffuse easily across lipid bilayer
- pH in small intestine is higher than pKa of aspirin - becomes ionised - slower absorption
- Ratio of ionised:non-ionised dictated by pH of environment relative to pKa of drug
What is ion trapping?
- The ionised form goes through the liver into systemic circulation
- Aqueous environment and trapped in ionised form
- Ion trapping creates another barrier to absorption
What 4 main factors influence drug distribution?
- Regional blood flow
- Extracellular binding (plasma protein binding)
- Capillary permeability
- Localisation in tissues
Outline the relationship between perfusion/activity of tissues with exposure/distribution?
- Well perfused tissues - exposed to higher concentration of drug
- Some tissues increase in perfusion when activity increases e.g. skeletal muscle
- Highly metabolically active tend to have a greater blood flow & denser capillary network
What proportion of acidic drugs bind to plasma proteins?
50-80%
What form of the drug can albumin bind to?
Both ionised and non-ionised
How can ionised aspirin easily pass through endothelial cells?
Through small water-filled (aqueous) gaps between the cells
What are the 3 types of capillaries and why are they important in drug distribution?
- Fenestrated - more permeable to drugs
- Continuous - water-filled gap junctions
- Discontinuous - large gaps between endothelial cells
Where do lipophilic drugs tend to localise and why?
- Fatty tissue e.g. brain, testes
* Not usually highly perfused - so very lipophilic environment
Outline drug excretion in the kidneys
- Drugs converted into water soluble molecules filtered in here
- Most of the excretion of xenobiotics done here
- However, most drugs enter urine via active secretion (not ultrafiltration) due to large, protein-bound drug complexes
- Active secretion of acids and bases in proximal tubule
- Lipid soluble drugs reabsorbed in proximal and distal tubules (passive diffusion)
Outline drug excretion in the liver
- Tends to be large molecular weight drugs
- Drug concentrated in bile
- Active transport - drugs use systems used for bile acids and glucuronides as they are non-polar and have a large molecule weight
- Secreted into intestines
- Enterohepatic cycling - drug/metabolite may be reabsorbed
- Drug persists in body for longer than expected
How can drugs be excreted, apart from the kidneys and liver?
- Lungs - expired air
- Gastrointestinal secretions
- Saliva
- Swear
- Milk
Why might treatment with IV sodium bicarbonate increase aspirin excretion?
- Increased urine pH
- Aspirin is ionised (equilibrium shifts right)
- Aspirin becomes less lipid soluble
- Less aspirin reabsorbed in proximal and distal tubules
- Increased rate of excretion
What is bioavailability?
- Proportion of the administered drug that is available within the body to exert its pharmacological effect
- Post-hepatic concentration
What is the ‘Apparent Volume of Distribution’?
- The volume in which a drug appears to be distributed
* Indicator of the pattern of distribution
What is clearance?
- Volume of plasma cleared of a drug per unit time
- Related to volume of distribution and the rate at which the drug is eliminated
- Incorporates excretion through all routes (kidneys, liver etc.)
