What are the fates of drugs in the body?
Absorption
Distribution
Metabolism
Excretion
What is absorption?
The process by which the drug enters the body from its site of administration and enters the general circulation
What is distribution?
The transport of drugs by the general tissues. This usually involves the drug leaving the blood and entering tissues.
What is metabolism?
The process by which tissue enzymes catalyze the chemical conversion of a lipid soluble drug into a less active and more polar form that can be readily excreted
What is excretion?
The process that removes the drug or its metabolites from the body
What factors affect drug absorption?
Solubility
Chemical stability
Lipid to water partition coefficient
How does solubility affect drug absorption?
The drug must be able to dissolve in an aqueous solution in order to be absorbed
How does chemical stability affect drug absorption?
Some drugs are destroyed by acid in the stomach or enzymes in the GI tract. In some cases, a compound is modified within the gut to release an active drug
How does lipid to water partition coefficient affect drug absorption?
Absorption usually occurs via simple diffusion across membranes. For a given drug concentration gradeint across a membrane, the rate of diffusion increases with the lipid solubility of the drug.
What is the partition coeffcient?
The ratio of the drug concentration in the membrane and concentration in water at equilibrium
What does the degree of ionisation depend on?
The pKa of the drug and the local pH
What is pKa?
The pH at which 50% of the drug is ionised and 50% of the drug is unionised
How can the proportions of ionised and unionised drugs be calculated?
Henderson-Hasselbalch equations:
Acid: pKa - pH = log(AH/A-)
Base: pKa - pH = log(BH+/B)
Where is the absorption of weak acids facilitated?
The pH of the stomach lumen.
Where does the majority of absorption occur?
In the small intestine due to the large surface area, due to the presence of villi
What do acidic drugs become in an acid environment?
Less ionised
What do basic drugs do in a basic environment?
Less ionised
What factors affect GI absorption?
GI motility - -rate at which stomach empties
pH at the absorption site
Blood flow to the stomach and intestines - increased by food
The way in which the tablet/capsule is manufactered
Physicochemical interactions
Transporters in the membranes of epithelial cells of the GI tract which facilitate drug absorption
What is oral avaliability?
The fraction of drug that reaches the systemic circulation after oral ingestion
What is systemic availability?
The fraction of drug that reaches the systemic circulation after absorption
What way of administering drugs provides 100% systemic availability?
IV
How can systemic availability be reduced by oral administration?
The drug can be inactivated by enzymes in the gut wall or liver before reaching the systemic circulation and body tissues in general
What are common routes of administration?
Oral Inhalation Buccal/sublingual Transdermal/subcutaneous IV Rectal IM
What routes of administration enter straight into the blood stream?
Buccal/sublingual Subcutaneous IV Rectal Intramuscular (IM)
What routes of administration require absorption?
Oral
What are some advantages to oral administration?
Simple, convenient, non-sterile, good absorption
What are some disadvantages to oral administration?
Inactivation of drugs by acid/enzymes
Food binding
Swallowing may be difficult
Must pass the metabolism
Where can drugs withing the systemic circulation move to?
Body fluid compartments
What are the types of body fluid compartments?
Plasma water - 2.8L Interstitial water - 11.2L Intracellular water - 28L Transcellular water - 1.4L Fat
What are the 2 states a drug molecule can exist in?
Bound or free
What state of drug can move body compartments?
Free drugs. Ionisedand unionised drugs that are not bound to a protein can move freely via diffusion.
What is the volume of distribution (Vd)
The apparent volume in which a drug is dissolved in the plasma membrane
What is the Vd of a drug that is administered IV?
Vd = dose/plasma concentration
What is more generally the equation to work out Vd?
Vd = amount of drug in the body/plasma concentration
What does a Vd of less than 10L imply?
The drug is largely retained in the vascular compartment - this occurs for drugs that are extensively bound to membrane proteins such as aspirin or warfarin
What does a Vd between 10 and 30L suggest?
The drug is largely restricted to extracellular water. This applies to drugs with a low lipid solubility e.g. gentamicin and amoxicillin
What does a Vd of more than 30L suggest?
There is distribution throughout the total body water or accumulation in certain tissues