Pharmacokinetics - AD Flashcards
What is pharmacokinetics?
Study of what the body does to a drug
What are the processes involved in drug entry to the body?
Absorption
Distribution
What are the processes involved in drug removal from the body?
Metabolism
Excretion
What are the routes of drug administration? What do they each mean?
Enteral - drug is delivered to the GI tract
Parenterel - drug is delivered through routes that are not the GI tract
What are some examples of enteral drug administration?
Oral
Rectal
What are some examples of parenterel drug administration?
Intravenous
Intramuscular
Subcutaneous
Inhalation
What is the most common route of drug administration?
Oral
Are drugs absorbed in the stomach? Why?
No
because it has a thick layer of mucous
Where does most of drug absorption occur? Why?
Small intestine
Has extremely large surface area
long transit time
What is the typical transit time of food in the small intestine?
3-5 hours
What does transit time of food in the small intestine depend on?
Motility - the contraction of smooth muscle in the small intestines to mix and propel the food along
What is the pH of the small intestine? What is the importance of this?
Slightly acidic, 6-7
Affects the proportion od drugs in ionised and unionised states
What are the different mechanisms of drug absorption in the small intestine?
Passive diffusion
Facilitated diffusion
Active transport, mostly secondary
Pinocytosis
What properties must a drug have in order to be absorbed by passive diffusion in the small intestine?
Lipophilic
Small, not ionic
How do drugs that are weak acids or bases exist in the small intestine?
Equilibrium between their ionised and unionised forms
How can drugs that are weak acids or bases be absorbed by passive diffusion in the small intestine?
Drug in unionised form is absorbed by passive diffusion
then because of the equilibrium, the ionised form is prontonated/deprotonated into the unionised form
Or by facilitated diffusion (later flashcards)
What properties do drugs absorbed by facilitated diffusion in the small intestine generally have?
Low lipid solubility, hydrophilic
Large
What is the name of the transporters responsible for facilitated diffusion of drugs in the small intestine?
Solute carrier transport proteins
What are the types of solute carrier transport proteins?
Organic anion transporters
Organic cation transporters
Where in the body are organic anion and cation transporters expressed?
Small intestine
Liver
Kidneys
What properties do drugs absorbed by secondary active transport in the small intestine generally have?
Low lipid solubility, hydrophilic
Large
What is the name of the transporters responsible for secondary active transport of drugs in the small intestine?
Solute carrier transport proteins
- organic anion transporters
- organic cation transporters
Which electrochemical gradients are used in the secondary active transport of drugs in the small intestine?
Sodium ions
What properties do drugs absorbed by pinocytosis in the small intestine generally have?
Extremely large
What are the groups factors affecting drug absorption in the small intestine?
Drug properties factors
GI properties factors
Drug metabolism in gut
What are the drug properties factors affecting drug absoprtion in the small intestine?
Lipophilicity
Size
Acid/base properties
Charge
What are the GI properties factors affecting drug absoprtion in the small intestine?
Total surface area
pH
Blood flow
GI motility, transit time
Density of transporters
Food
Enzymes
What inreases blood flow to the small intestine?
Eating
What decreases blood flow to the small intestine?
Exercise
Heart failure
Shock
What increases GI motility?
Diarrhoea
What decreases GI motility?
Eating
How can small intestine pH and enzymes affect drug absorption?
Can destroy some drugs
reducing their absorption
How can the presence of food affect drug absorption?
Can both increase and decrease absorption for different drugs
Where does most of the drug metabolism in the gut occur?
Liver
How do drugs first reach the liver?
Absorbed into small intestine capillaries
travel through the hepatic portal vein to the liver
What is the name of the drug metabolism occurring in the liver after it’s just been absorbed? Why?
Hepatic first pass metabolism
Because it occurs in the drug’s first passage into the body
What happens in hepatic first pass metabolism?
Some drugs passing through veins and capillaries of the liver
enter cells and are metabolised by enzymes
What are the types of enzymes involved in hepatic first pass metabolism?
Cytochrome P450s - Phase 1
Conjugating enzymes - Phase 2
What is bioavailability?
Relative amount of drug that reaches systemic circulation
What does bioavailability reflect?
Reflects all the barriers to absorption of the drug
in its particular route of administration
What is the reference route of administration used in bioavailability? Why?
IV
because all of the drug reaches the systemic circulation
What is oral bioavailability?
Relative amount of drug that reaches systemic circulation for drugs given via oral route compared to giving them via IV route
How is oral bioavailability calculated?
Area under curve for oral route curve
______________________________
Area under curve for IV route curve
curve is y axis-plasma drug concentration against x axis-time
What is the symbol for oral bioavailability?
F
What are the range of values of oral bioavailability?
0 to 1
What is drug distribution?
The process of drug molecules reaching their target sites in cells from the systemic circulation
How are drugs distributed in the body?
In blood in arteries
then diffuse out of capillaries into intersitital fluid and then to their target cells and then to their target site on those cells
What are the factors of drug distribution?
Blood supply to target tissue/capillary density to target tissue
Capillary permeability
Drug lipophilicity
Drug binding to plasma proteins, tissue proteins
What are the different types of capillaries based on their permeability, in order from least permeable to most permeable?
Continuous
Fenestrated
Sinusoid
What is the structure of continuous capillaries
Their endothelial layer and basement membrane doesn’t contain any holes or gaps
What is the structure of fenestrated capillaries?
Their endothelial layer contains holes
What is the structure of sinusoid capillaries?
Both the endothelal layer and the basement membrane have gaps
What are some examples of organs that contain fenestrated capillaries?
Intestines
Kidneys
What are some examples of organs that contain sinusoid capillaries?
Liver
Spleen
What are some examples of organs that contain continuous capillaries?
Brain - blood-brain barrier
How do lipophilic drugs distribute in the body?
Can passively diffuse across capillary walls, cell membranes etc. to target site
How do hydrophilic drugs distribute in the body?
Leave the capillaries through fenestrations or sinusoids
may become uncharged by pH of tissue and then passively diffuse across cell membranes
or if remain charged, can be carried by organic anion or cation transporters across cell membranes if they’re present
What are some examples of plasma proteins that drugs may bind to?
Albumin
Lipoproteins
Immunoglobulins
How do plasma proteins affect the plasma drug concentration?
Reduce the free drug concentration
What proportion of the drug is bound to plasma proteins in the blood? Why?
Equilibrium between
drug + protein protein-drug complex
What form of the drug in the blood is able to bind to target sites and cause an effect?
Only the free drug molecules can do this
What are the different body fluid compartments?
Plasma water
Extracellular water = plasma + interstitial water
Total body water = plasma + intersitital + intracellular water
What is volume of distribution referenced to?
Plasma drug concentration
How is volume of distribution calculated?
Total amount of drug in body
____________________________
Plasma drug concentration at time 0
What do smaller volume of distribution values mean?
Higher drug concentration in plasma
less penetration of intersitital and intracellular fluid
What do large volume of distribution values mean?
Lower drug concentration in plasma
more penetration of interstitial and intracellular fluid
What are the units of volume of distribution?
Litres assuming standard body weight
Litres/kg for specific body weights
What are the over-simplifications made by the volume of distribution?
That all the different body fluid compartments behave similarly
That the drug is evenly distributed throughout the whole body
That the drug is fully distributed at time 0
