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












