Drug distribution Flashcards
Plasma protein binding
Carriers for poorly soluble metabolites
- drugs drugs bind to these + are transported around circulation
- reversible binding
- influence drug pharmacokinetics
How do drugs bind to serum albumin (plasma protein)
Thermodynamic motion leads to chance collision
- Electrostatic binding forces can be overcome by thermal energy
- 90% drug bound is = 90% of molecule being bounded of the time
Competition for plasma protein binding sites lead to…
drug interactions
What drugs can access blood brain barrier
Lipophilic/transported drugs can access
Blood brain barrier
Effective diffusional barrier
- tight junctions between endothelial cells, pericytes + glial limitans are barriers to drug escape
How can drug enter placenta
Drug must pass into maternal blood pool + enter foetal circulation (passive diffusion/active transport)
- risk of teratogenic/embryotoxic effects
Which drugs can/ cannot enter placenta
Lipophilic drugs can
Drugs with high plasma protein binding affinity do not
How do drugs enter breastmilk
Alveolar apical cells form a tight junction limited lipid barrier between capillaries + alveolar lumen
- diffusion into milk limited by lipophilicity + size
Adipose tissue is a major reservoir for…
Lipophilic drugs
Where is adipose tissue
Skin (subcutaneous), around intestinal organs (visceral), breasts + bone marrow
What s adipose tissue composed of
Adipocytes - cells with large intracellular vacuoles filled with lipids
- lipid soluble drugs can accumulate in reservoir
- increase in adipocyte, size in obesity
Which compartments are drugs distributed
Extracellular fluid (plasma, interstitial fluid, lymph)
Intracellular fluid (cell contents)
Transcellular fluid (CSF, peritoneal, intraocular, synovial etc.)
Fat
Bound to protein
Volume of distribution
Apparent volume of plasma that would accommodate total drug amount at the measured plasma concentration
Calculate Vd
total amount of drug/plasma concentration
If Vd is more than 40 litres
Indicates some storage of drug in tissue
If Vd is less than 15 litres
drug is largely restricted to plasma + interstitial fluid
How can critically-ill patients alter distribution parameter
Changes in capillary permeability due to inflammation
Decrease in blood pressure and organ perfusion in septic shock
Fluid resuscitation increases Vd
How can pre-existing disease alter distribution parameter
Hepatic disease causes decrease in serum albumin levels
Renal dysfunction changes fluid volumes
How can obesity alter distribution parameter
Ideal versus actual body weight
Accumulation of lipophilic drugs and other xenobiotics (e.g. organophosphate poisoning)
How can active transport alter distribution parameter
Import of drugs across lipid barrier by transporters
Export of drugs from cells by P-glycoproteins
Non-linear relationship between plasma extracellular + intracellular concentrations
Distribution of drug after administration is determined by
Reversible binding to plasma proteins
Perfusion of tissue by blood
Structure of vascular endothelium
Lipophilicity of drug
When choosing antibiotic, must consider…
site of infection + drug distribution
Aminoglycosides are hydrophilic, can they accumulate in adipose tissue
No - danger of toxicity
