Pharmacokinetics Flashcards
What does ADME stand for
Absorption
Distribution
Metabolism
Excretion
Why is pharmacokinetics important
Determines the dose of the drug available to tissues
compare systemic to local administration
systemic = to entire organism Local = restricted to one area of the organism
Compare enteral to parenteral administration
Enteral = gastro-intestinal admin Parenteral = outside GI tract
What are the main types of administration
Dermal Intramuscular Subcutaneous Intraperitoneal Intravenous Inhalation Ingestion
What are the two ways that drugs move around the body and give examples
Bulk flow transfer e.g. bloodstream
Diffusional transfer e.g. molecule by molecule
What does the form that drugs exist in depend on
Ratio of ionised (polar) to non-ionised depends on the pH as drugs are mostly weak acids or bases
How does pH contribute to the absorption of drugs
Determinant of absorption across lipid membranes
Weak acids are more unionised in acidic environment, weak bases are more unionised in alkaline environments
Do charged or non-charged molecules diffuse easier across lipid membranes and why
Unionised / non-charged forms are more lipid-soluble so diffuse easier
What is the Henderson-hasselbalch equation
pKa = pH + log10 [H+]/[A-]
pKa= pH + log10 [BH+]/[B]
What factors influence drug distribution
Regional blood flow
Extracellular binding (plasma-protein)
Capillary permeability
Localisation in tissues
Why may capillary permeability differ
Tissue alterations
renal, hepatic, brain/CNS, placental
What is the distribution of regional blood flow
liver - 27% Kidneys - 22% Muscles - 20% Brain - 14% Heart - 4%
What is the significance of plasma protein binding
The greater the proportion, the less is free to access to tissue and leave the blood
50-80% of acidic drugs are bound
Why are water soluble drugs less well distributed across the body
Poor access to tissues and dependant on saturable carrier proteins for access to tissues
Describe and give an example of a discontinuous barrier
Big gaps between capillary endothelial cells
e.g. liver
Describe and give an example of a fenestrated barrier
Circular windows within endothelial cells that allow small molecular weight substances through
e.g. kidney glomerulus
What are the type of junctions between cells in a continuous capillary
water-filled gap junction (only for small molecules)
What are the type of junctions in the blood brain barrier
Tight junctions
Why are only small amounts of non-ionised drug delivered to body fat
Blood flow is very low (2%)
What is the oil/water partition coefficient
How well the drug deserves in fat vs water.
How does oil/water partition coefficient affect how it leaks into the blood
A high coefficient suggests that even a small percentage reaching the body fat will accumulate very effectively and therefore it will leak back slowly due to poor blood flow and preference of the drug to fat e.g. GA
What are the two major routes of drug excretion
Kidney - most drugs
Liver - drugs may be concentrated in the bile (usually large)
Describe the basic route of drugs through the kidney
Glomerular filtration (usually low mw) Active secretion into the tubule Passive reabsorption back into the blood
What does the rate at which drugs are excreted through the kidney depend on
GFR dependent on size
Active secretion dependent on available transporters
Reabsorption is dependent on urine pH and the extent of metabolism
What is enterohepatic cycling and what does it lead to
Drugs/metabolites are excreted into the gut (ileum) via bile and then reabsorbed and taken to the liver to be excreted again leading to drug persistence
What are some other routes of drug excretion
Lungs Skin GI secretions Saliva Swear Milk Genital secretions
Define bioavailability
Proportion of the administered drug that is available within the body to exert its pharmacological effect
Define apparent volume of distribution
The volume in which a drug appears to be distributed (indicator of the pattern distribution)
Define biological half-life
Time taken for the concentration of the drug in the blood/plasma to fall to Half its original value
Define clearance
Blood clearance is the volume of blood cleared of a drug in a unit of time
How do drugs cross lipid barriers
Diffuse across the membrane
Diffusion across aqueous pores
Carrier mediated transport
Which mechanism of crossing a lipid barrier is least relevant and why
Diffusion across aqueous pores as the drug must be small enough to cross
At what pH are drugs more ionised
acids - higher than pKa
bases - lower than pKa
Why is pH important for drug absorption
Drugs become very localized within body compartments
e.g. aspirin will diffuse into the bloodstream easily, but will not diffuse very well across membranes and into tissues
