Pharmacokinetics Flashcards
What are the four main processes in Drug Therapy?
Absorption (mainly through GI tract) -In
Distribution -In
Metabolism (elimination) -Out
Excretion (elimination) -Out
How can mathematical models be useful?
Mathmatical models are useful in describing, predicting or approximating changes in drug concentration over time throughout the body.
Drugs are..
…Exogenous signalling molecules.
What is enteral drug delivery?
Delivery into internal environment of the body through the GI tract. This can be oral, sublingual or rectal.
What is parenteral drug delivery?
Delivery via all other routes that are not the GI -inc.
Intravenous
Subcutaneous
Intramuscular
What is the mnemonic used to remember the routes of drug administration?
Oral
Intravenous
Intramuscular
Transdermal
Intranasal
Sublingual
Subcutaneous
Inhalation
Rectal
How are drugs absorbed?
Most drugs are taken orally because this is most convenient.
Normally little absorption in stomach (SA is around 0.75m^2)
The drug then mixes with chyme and enters small intestine.
Small intestine is around 6-7m in length by 2.5cm diameter so the total SA for absorption is around 35m. (a LOT larger than the stomach).
There is constant GI movement and mixing which presents different drug molecules to the GI tract.
What is the average transit time for drug absorption in small intestine?
3-5hrs. But can vary from 1-10hrs.
pH of small intestine is also weakly acidic (pH 6-7)
How different mechanisms are used to absorb drugs on a molecular level?
Passive diffusion
Facilitated diffusion
Primary / Secondary Active Transport
Pinocytosis (endocytosis and exocytosis -mostly for very large molecules such as insulin)
What is passive diffusion? What kinds of molecules use this method of transport?
This is the most common way for drugs (especially lipophilic drugs and weak acids/bases) to pass across membranes.
Lipophilic drugs (eg steroid diffuse directly down the conc. gradient into GI capillaries.
Over the transit time of 4-5hrs and a very large SA, ionised species diffuses into GI capillary bed easily.
The non ionised ones will then become protonated (because need to have equilibrium of ionised:not ionised in GI tract) and cross the membrane.
EG Valproate which has pKa of 5 so, in the gut at pH6 10% of the Valpoate will be ionised.
What is facilitated diffusion? What kinds of molecules use this method of transport?
A number of nutrient and signalling molecules with low lipid solubility and a net residual ionic charge cross the GI epithelia in this manner.
This is a passive process given by the electrochemical gradient for that molecule. The molecules travel through solute carrier proteins.
What is secondary active transport? What kinds of molecules use this method of transport?
SLCs can also enable drug transport in GI by secondary Active transport.
This does not use ATP -Transport is instead driven by pre-exisiting electrochemical gradients across the GI epithelial cell membrane.
EG Fluoxetine/Prozac is an SSRI antidepressant that is co-transported with Na+ ion..
What are SLCs? What two categories are they divided into?
Solute Carrier proteins. These are divided into Organic Anion Transporters (OAT) and Organic Cation Transporters (OCT).
Factors Physiochemical affecting drug absorbtion?
GI length and surface area
Drug lipophilicity /pKa
Density of SLC expression in GI
What are the physiological features of the GI tract that affect drug absorption?
Blood flow- This increases post meal and drastically reduces with thick/anxiety and with exercise.
GI motility- This is slow post meal and rapid with severe diarrhoea.
Food / pH: Food can reduce/increase the uptake. Low pH will destroy some drugs.
What other factors affect drug absorption?
First Pass metabolism by GI and Liver.
Gut Lumen : Gut/ Bacterial enzymes can denature some drugs
Gut wall / Liver : Some drugs are metabolised by two major enzyme groups: Cytochrome P450s (phase I enzymes) and Conjugating (Phase II enzymes)
There is a much larger expression of phase I and II enzymes in the liver.
‘First pass” metabolism: reduces availability of drug reaching systemic circulation and therefore affects their therapeutic potential.
What is Bioavailability?
Bioavailability is a fraction of a defined dose which reaches its way into a specified body compartment.
CVS is the most common reference compartment. For CVS/ circulatory compartment, if given using IV there is 100% bioavailability.
How do you work out bioavailability?
Bioavailability = amount of drug reaching systemic circulation / Total amount of drug administered. (no. between 0-1)
a comparison of the bioavailability of the same drug given in different ways (often compare IV to oral) informs the choice of administration route.
Primary way drugs get circulated through the body?
Through the circulatory system.
First stage…
Bulk Flow -Large distance via arteries to capillaries
Diffusion -Capillaries to interstitiel fluid to cell membranes to targets
Barriers to Diffusion -Interactions / local permeability / non-target binding (muscle and adipose)
What barriers are there to diffusion?
-Interactions / local permeability / non-target binding (muscle and adipose)
How are drugs distributed through the body?
Differing levels of capillary permeability enable variation in entry by charged drugs into tissue interstitial fluid and from there into target sites.
The amount of capillaries in different places also allow for variation in distribution. For example, drugs are likely to get to capillary dense tissues such as heart and kidney much faster than to bone and adipose.
What are the major factors affecting drug distribution?
Drug molecule lipophilicity / `Hydrophilicity.
-If a drug is largely lipophilic it can freely move across membrane barriers. Whereas, if a drug is largely hydrophilic the journey across membrane barriers is dependant on factors described for absorption (such as capillary permeability, drug pKa and local pH and the presence of OATs and OCTs).
Degree of drug binding to plasma proteins and/or tissue protein.
-In circulation, many drugs bind to proteins such as albumin, Globulins, Lipoproteins acid and glycoproteins.
The mass or volume of tissue and density of biding sites within that tissue.
What is the simple model of drug movement between body fluid compartments?
Drug molecules are solutes in Body fluid compartments.
This model shows the movement of water between three main compartments: plasma, interstitial and intracellular water.
(Interstitial and Plasma are extracellular water.) This makes movement of solutes much easier to track and assess.
What are the factors that influence speed of absorption?
Capillary Permeability
Drug pKa and local pH
Present of OATs/OCTs