ESA1 PK Flashcards
Pharmacokinetics can be summarised as:
- Absorption
- Distribution
- Metabolism
- Elimination
How can drugs be administered?
1) Enterally
- Delivery into internal environment of the body- GI tract
- Sublingual
- Oral
- Rectal
2) Parenteral
- Delivery via all other routes that are not the GI
- Intravenous
- Subcutaneous
- Intramuscular
Drug administration mnemonic
Oral
Intravenous
!
Intramuscular
Transdermal
-
Intranasal
Subcutaneous
-
Sublingual
Inhalation
Rectal!
majority of drugs given by which route
oral route
describe the absorption of drugs via the oral route
- drugs move through GI system
- Drugs mixes with chyme and enters the intestine
- Intestine 6-7m in length and 2.5cm in diameter
- Total SA for absorption= 30-35m2
- GI peristalsis ensures mixing of the drug–> meaning drug is presented to GI epithelia
-
Drug absorption in the small intestine (typical trait time -time it takes to pass from stomach to the end of the s.intestine- 3-5h
- Drug has a long time to be absorbed at some point in the s.intestine
- drug absorbed into the heptoportal system
- into the venous system
- to the right ventricle
- to the lungs
- to the left venrtricle
- arterial circulation
drug absorption via
- Passive diffusion
- Facilitated diffusion
- Primary/secondary active transport
- Pinocytosis
Passive diffusion of drugs during absorption
- Common mechanism for lipophilic drugs and weak acid/bases
Lipophilic drugs e.g. steroids diffuse directly down concentration gradient into GI capillaries
Weak acids (protonated- uncharged) /bases (deprotonated)
drugs pass more readily though the membrane if
uncharged
- Protonated species can therefore pass through the membrane
- Deprotonated species are charged and cannot pass through the membrane
pKa relationship with pH
- If the pH of the solution is less than the pKa value then the group will be protonated
- If the pH of the solution is more than the pKa then the group will be deprotonated
example of pKa relationship with pH
i.e. if the drug has a pkA of 5 (valproate- antiepileptic drug) in the s.intestine (pH 6), then most of the drug will be deprotonated.
- Only 10% of the valproate is protonated
- Protonated (uncharged)= lipophilic = can cross GI epithelia
faciliated diffusion
Molecules (or solutes) with net ionic + or – charge (charged molecules) within GI pH range can be carried across epithelia via solute carrier (SLC) transport
–> Passive process based on electrochemical gradient for molecule
SLCs are either Organic Anion Transporters (OATs) or Organic Cation Transporters (OCTs)
- Large family expressed in all body tissue
- Pharmacokinetically important for drug absorption and elimination
- Highly expressed in GI, hepatic and renal epithelia
Secondary active transport (SLC transport)
SLC can also enable drug transport in GI by secondary active transport
- Doesn’t utilise ATP
- Transport driven by existing (ATP created) electrochemical gradient across GI epithelial membrane e.g. Renal OATs and OCTs
e.g.
- Fluoxetine/Prozac* - SSRI antidepressant co-transported with Na+ ion
- Penicillins* - co-transported with H+ ion
Factors affecting drug absorption: Physiochemical factors
- GI length and surface area
- Drug lipophilic/ pKa (how protonated (uncharged) the drug is at GI pH)
- Density of SLC expression in GI
what sort of molecules are most easily absorbed (by passive diffusion)
lipophillic drugs
Protonated drugs (i.e. when the pH is higher than the pKa)
Factors affecting drug absorption: GI Physiology
- Blood flow
- Increase absorption post meal- drastically reducing shock anxiety and exercise (get cramp because blood in intestines and not muscle)
- GI motility
- Slow absorption post meal
- Food/ pH
- Food can reduce/increase uptake of drug
- Low pH destroys some drugs reducing uptake
other factor which affects drug absorption into the blood stream
firts pass metabolism by the GI and liver
First pass metabolism by GI and Liver
Reduces availability of drug reaching systemic circulation- therefore affects therapeutic potential
-
Gut lumen
- Gut/ bacterial enzymes can denature some drugs
-
Gut walls/ liver
- Some drugs metabolised by two major enzyme groups (much larger expression in the liver)
- Cytochrome P450s- Phase I enzyme
- Conjugating- Phase II enzymes
- Some drugs metabolised by two major enzyme groups (much larger expression in the liver)
Bioavailability
Fraction of a defined dose which reaches its way into a specific body compartment - systemic circulation (blood) is the most common reference compartment
- informs choice of admin routes
Bioavailability equation
total drug given IV reaching systemic circulation will be 100%, therefore other routes are compared to this
how to calculate bioavailability
proportion of the amount given orally that reaches systmic ciruclation
what is drug distribution
How drugs journey through the body
- To reach and interact with therapeutic and non-therapeutic target
- Interaction with other molecules- affect on pharmacodynamics
first stage of drug distribution
1) Bulk flow- large distance via arteries to capillaries
2) Diffusion- capillaries to interstitial fluid to cell membrane to targets
3) Barriers to diffusion- interactions/ local permeability/ non-target binding
Drug diffusion across capillaries
- Differing levels of capillary permeability
- Variation in entry by charged drugs into tissue interstitial fluid/target site
- Capillary membranes also express endogenous transporter and OAT/OCTs
Major factors affecting drug distribution
1) Drug molecule lipophilicity/ hydrophilicity
- If drug is largely lipophilic can feely move across membrane barriers
- If drug is largely hydrophillic (mostly protonated at Gi pH) journey across membrane barriers dependent on factors described for absorption
- Capillary permeability
- Drug pKa and local pH
- Presence of OATs/ OCTs
2) Degree of drug binding to plasma and tissue protein
- In circulation many drugs bind to proteins e.g.
- Albumin (globulins)
- Lipoproteins (acid glucoproteins)
Degree of drug binding to plasma and or tissue proteins Albumin as an example
- Only free drug molecules can bind to target site
- Binding to plasma/ tissue proteins (albumin) decreases free drug available for binding
- Plasma/ tissue protein bound drugs act as a dynamic reservoir
- Binding forces not strong (bound/unbound in equilibrium)
- Binding for a given drug can be up to 100% e.g. aspirin (50%)
- Varying number of binding site for given drug
- Competition for binding site affects free plasma conc and pharmacodynamics
body fluid compartments
3 main compartments
- Plasma
- Interstitial
- Intracellular
Increasing penetration by drug into interstitial and intracellular fluid compartments leads to:
- Decreasing plasma drug concentration
- Increasing Vd
Apparent volume of distribution (Vd)
is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma
volume of distribution equation
smaller Vd values
less penetration of interstitial/intracellular fluid compartments
- more drug stays in the plasma
Larger Vd values
- greater penetration of interstitial/ intracellular fluid compartment
- less drug stays in the plasma
sumamry of phase I and II metabolism
main aim of phase I and II metabolism is to increase ionic charge to make the drug more hydrophilic/lipophillic - so it can be excreted by the kidneys
- some drugs can be excreted after phase I motabolism
- others need both phases
genetic polymorphisma nd CYP450
-
Codeine and CYP2D6
- CYP2D6 not expressed in 7% Caucasians
- Prodrugs activated by phase I metabolism to active species
- CYP2D6 is highly polymorphic
- Categorised into
- Poor- may not experience pain relief (codeine has a lower affinity to u-opioids receptors than morphine)
- Normal
- High
- Ultrarapid metabolisers (hyperactive in 30% east africans)
- Categorised into
- CYP2D6 is highly polymorphic
Renal capillaries
- Fenestrated
- Increased permeability to enable optimised exchange of ions/molecules
passive tubular reabsorption and weak acid/bases
Same as s. intestine but reversed.
Remember drugs must be neutrally charge to be passively reabsorbed.
Drugs reabsorption in the DCT that are Weak acids
- Low pH (acidic urine in DCT): increases absorption of weak acids
- Protonate them, meaning they become neutral and can be reabsorbed
Drugs reabsorption in the DCT that are Weak bases
- High pH (basic): increase absorption
- Lose proton, becomes naturally chargedà reabsorption
What is clearance?
The volume of plasma cleared of drug per unit time
- Measured in ml/min
- Total drug clearance- consists of that from all routes
Drug half life t12 equation
example of drug half life
Thus, after two half-lifes, 25% of the drug is left; after three, 12.5%; and after 4 half-lives, 6.25%.
The half-life determines the length of the drug’s effect.
First order kinetics (linear kinetics)
- Elimination of a constant percentage (or fraction) of the drug per unit time. (if a large functional reserve of enzymes)
- That is - if there is Large Functional Reserve and Plenty of Phase I/II Enzyme sites
- Plenty of OAT/OCT Transporters
- For most drugs, the elimination occurs at a rate directly proportional to the concentration of the drug—i.e., the higher the drug concentration, the higher its elimination rate (e.g., 50% per unit time, as shown in the figure).
- Rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time
