drug distribution Flashcards
distribution
- a drug must be available for biological action and distributed t the tissues once absorbed
- to be active it must then leave the blood stream
drug distribution refers to the …
reversible transfer of a drug between the blood and extravascular fluids and tissues of the body
factors affecting tissue distribution
plasma protein binding tissue perfusion membrane characteristics transport mechanisms diseases and other drugs elimination
membrane characteristics
- blood-brain barrier
- blood testes/ovary barrier
- lipid soluble drugs are able to pass the blood-X barrier
- active transport
plasma protein binding
many drugs bind to plasma proteins
only the unbound drug is biologically active
binding is reversible
saturability of binding is important
amount of bound drug can be changed by
renal failure
hypoalbuminaemia
pregnancy
other drugs - could also be protein bound and displace the first drug
why does protein binding matter
- in order to be an important factor, the drug must be more than 90% bound and the tissue distribution small
therapeutic range
range over which drugs are active
it is important to characterise certain parameters such as volume of distribution, clearance and half life because many drugs have an ideal therapeutic range over which they are active
apparent volume of distribution
volume of distribution is the volume of plasma that would be necessary to account for the total amount of drug in a patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma. The result are expressed in terms of litres per kilogram.
factors affecting volume of distribution
Drugs with a high lipid solubility, low rates of ionisation, or low pp binding have larger vol of distribution.
Drugs which are polar, more highly ionised or have high pp protein binding have a small volume of distribution.
Volume of distribution is increased by renal failure and live failure and decreased in dehydration.
the greater the volume of distribution,
the greater the ability of the drug to diffuse into and through membranes
what should the volume of distribution be in theory
42L
• If it stays in the extracellular fluid but can not penetrate cells = 12L.
• If highly protein bound = 3L (warfarin).
• If sequestered in extravascular lipid compartment >40L (THC, lithium).
define clearance
Clearance is defined as the theoretical volume from which a drug is completely removed over a period of time.
measured in ml/min
it is a measure of elimination
what is clearance dependent on
• Dependent on concentration and urine flow rate for renal clearance.
Dependent on metabolism and biliary excretion for hepatic clearance.
define half life
time taken for the drug concentration in the blood to decline to half of the current value.
half life depends on
volume of distribution and rate of clearance.
prolongation of the half life will …
increase the toxicity of a drug.
• due to reduction in clearance (due to renal impairment - this is the most common reason, as age increases, renal ability for clearance decreases)
• due to a large volume of distribution (amiodarone)
chronic administration
- To have a therapeutic benefit most drugs needed to be given chronically (slowly get blood levels up to therapeutic range) - unless condition is acute and drug is needed to be active quickly
- Plasma levels of a drug take many doses before they stabilise, usually 4-5 half-lives.
- This may necessitate a loading dose.
- It is important to know how a particular drug will build up in the body.
steady state concentration
plasma levels rise slowly towards therapeutic range
drug elimination
the removal of active drug and metabolites from the body.
• This determines the length of action of the drug.
drug elimination is made up of which 2 parts
Made up of 2 parts:
• Drug Metabolism (usually in the liver)
• Drug Excretion (usually in the kidney but also biliary system/gut, lung, milk)
what is the primary organ of drug excretion
the kidneys
renal damage is important in causing drug toxicity
3 principle mechanisms in drug excretion
○ Glomerular filtration (the most important)
○ Passive tubular reabsorption
○ Active tubular secretion
glomerular filtration
• All unbound drugs will be filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large.
• Any factors that affect the glomerular filtration rate will reduce the clearance of a drug:
Dehydration, illness, medicines (e.g. ace inhibitors, diuretics(can cause dehydration which then affects GFR), ibuprofen, )
active tubular secretion
• Some drugs are actively secreted into the proximal tubule (acidic and basic compounds).
This is the most important system for eliminating protein bound cationic and anionic drugs.
passive tubular secretion
• As the filtrate moves down the renal tubule any drug present is concentrated.
• Passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation.
• Passive diffusion occurs in the distal tubule and collecting duct.
• Only un-ionised drugs such as weak acids are reabsorbed.
Can also be affected by renal failure.
As drugs move through the tubules in the kidney, urine becomes more concentrated as water is reabsorbed and the concentration of the drug increases. If the drug is nephrotoxic this can cause renal failure.
biliary secretion
- Drugs may be passively or actively secreted into the bile.
- Biliary secretion accounts for 5-95% of drug elimination for many drugs.
- Many drugs are then reabsorbed from the bile into the circulation. This is called entero-hepatic circulation.
- It continues until the drug is metabolised in the liver or excreted by the kidneys.
conjugation
• Metabolism in the liver often leads to conjugation of the drug.
• The conjugated drug is not reabsorbed from the intestine.
Damage to the liver may reduce the rates of conjugation and biliary secretion and so allow the build up or reabsorption of the drug with resultant toxicity.
