pharmokinetics Flashcards
what does ADME stand for
Absorption Distribution Metabolism Excretion
access drug delivery
Access can be direct to site (easier for things like skin eye and gut) or indirect (via circulation but this introduces problems of dilution and dose)
different routes of adminstration of drugs
-inhalation
-oral
-rectal
-injection
-transdermal
(the properties of the drug effect this)
Absorption
all routes of adminstration require this step, except ravenous injection
- the drug must cross a lipid barrier to enter the blood it does this by either passive and active transport
-body is a closed system and blood makes continuous passes around the vascular system
what determines drug distribution
-Binding to plasma proteins
Reversible binding can carry drug around the circulatory system
Very high affinity binding can limit escape from plasma meaning there can be problems with reaching targets
- The tightness and permeability of the endothelial cells in blood vessels impact how easily drugs move from the bloodstream into tissues. Pores between endothelial cells in most vessel beds
Some special cases: blood brain barrier (tightly pakced), placenta (loosely packed)
-its ability to accumulate in different tissue depots, its binding to proteins, and its interaction with adipose (fat) tissue.
how blood flow effects distribution
Highly perfused (refers to how well the blood supply is) tissues, such as the heart, lungs, liver, kidneys, and brain, receive drugs quickly, leading to rapid accumulation and fast therapeutic effects.
Poorly perfused tissues, like muscles and skin, accumulate drugs more slowly due to reduced blood flow.
Lipophilic drugs tend to accumulate in adipose tissue, which, despite its lower perfusion, acts as a long-term reservoir, releasing the drug gradually over time.
Tissues with negligible blood flow, such as teeth, hair, bones, tendons, and cartilage, see minimal drug accumulation, except in cases of direct local application or specific drug interactions.
metabolism
-the liver metabolises drugs
-it does this into steps
-Redox reactions to add charge and/or reactive centres (makes the molecule more reactive for step 2)
-Conjugation reactions to add bulky groups
(make more water soluble so its easier to excrete)
Excretion of drugs
Final removal of the drug from the body
Mainly in the urine via the kidney
Some large drugs excreted in bile
Three key stages:
Passive filtration- Plasma is forced from blood into Bowman’s capsule of the tubule. Any drug in free solution will be passively carried over into the filtrate.
Active secretion- Transporter proteins extract drug from blood and drive into filtrate (using counter-ion transport and ATP hydrolysis). Drug can be concentrated.
Reabsorption- Lipid soluble drugs can diffuse back out of the filtrate and into the blood.
time vs drug plasma concentration
Concentration in plasma rises during absorption phase, peaks, then declines due to elimination
simplifications we use when measuring
time vs drug plasma concentration
We cannot realistically measure drug concentration at target site
Plasma concentration is more accessible
Assume a direct correlation between plasma concentration, concentration at the target, and drug effect
Simplify the body into compartments
Central compartment is the systemic circulation
Therapeutic window:
Plasma concentration range spanning minimum required for therapeutic effect, and onset of side effects
Relationship to plasma concentration may not hold if (challenge)
Effect is mediated through a metabolite
Effect is irreversible
Kinetics in the target compartment is different from that in blood
challenges with narrow therapeutic range
Difficult to use
Patient may need frequent therapeutic drug monitoring:
therapeutic effect, side effect, or blood level
Disposition
what happens to a drug after administration
absorption in the small intestine
Most drugs are absorbed in the small intestine
it has a:
Long residence time
Large surface area
Good blood supply
Transporters for active transport
Favourable pH
Microbiome
Incomplete absorption
The hepatic portal system
After crossing the gut epithelium the drug enters the hepatic portal system
Network of blood vessels that cover the stomach and small intestines
Carry absorbed nutrients (and drugs) from the gut straight to the liver
issue with first pass metabolism
reducing their effectiveness when taken orally. These drugs may require alternate routes of administration (e.g., intravenous, sublingual) to bypass the liver and avoid extensive metabolism.
what is first pass metabolism
First pass through the liver from the hepatic portal system allows metabolism of drug as it diffuses through to the hepatic vein
Some of the administered dose may be lost
Other routes of administration avoid this problem
Bioavailability
is a measure of how much drug that is administered reaches the systemic circulation
Fraction
Percentage
systemic circulation
Closed system of arteries, capillaries and veins
Oxygenation and nutrient supply to tissues
Clearance of waste products
Once drug is through the liver it circulates everywhere
structure of capillaries
Capillary structure varies between tissues
Continuous have no gaps within cells
Solutes must pass through intercellular clefts
Fenestrated have “windows” within endothelial cells
Solutes can diffuse out
Discontinuous have large gaps between and within cells and discontinuous basement membrane
Free movement of even large solutes
(1) to the lean tissues
As blood flows through most tissues (muscle, skin, lungs, heart etc.) hydrophilic drug will escape through intercellular gaps.
Lipophilic drug can freely escape between and across cells
(2) to the brain
the brain has a specialised structure known as the blood brain barrier which tightly regulates exchange of solutes
Hydrophilic drug must be transported
To the adipose (fat) tissue
Adipocytes are filled with lipid vacuoles, where lipophilic drugs can accumulate
targeting
All tissues and anatomical systems are perfused by the blood
Reaching a specific target molecule (or even organ) difficult
Have to accept that pharmacological action will be widespread
Drug clearance
Every pass through the circulatory system means a pass through the liver and kidneys
Drug is cleared or “extracted” on each pass
Extraction ratio and clearance can be calculated
Passing through the liver
Hepatocytes metabolise drug with CYP450 and UGT enzymes
Reduced concentration of parent drug on exit
Metabolites also released
May be pharmacologically active
Some drugs may also be excreted in bile
Passing through the kidney
Passive filtration and active secretion clear drug to urine
Metabolites from liver are more water soluble, and also cleared
Final elimination step
Measures of elimination
Elimination can be measured in several ways
Half life
Time taken for plasma concentration to decrease by half
Clearance
The apparent volume of plasma cleared of drug in a unit of time
Extraction ratio
The plasma concentration after passage through the organ divided by the concentration before entry (i.e. fraction lost)
