Lecture 16- Pharmacokinetics I Flashcards
pharmacokinetics can be summarised by (4)
- Absorption
- distribution
- metabolism
- elimination
drug in
Absorption
Distribution
Drug out
metabolism
elimination
how can drugs be administered (2)
1) enterally
2) parenteral
enteral routes
deliveraly into intervenal environemnt of the body - GI tract
- sublingual
- oral
- rectal
parenteral
delivery via any other route that are not GI
Drug administration mnemonic
Oi! It is Sir!
Oi! It is Sir!
oral
intravenous
intramuscular
transdermal
intranasal
subcutaneous
sublingual
inhalation
rectal
majority of drugs given via
oral route
oeal route
- 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 drugà meaning drug is presented to GI epithelia
typical trait time (time it takes to pass from stomach to the end of the s.intestine) for oral route
3-5 hours
- long time to be asborbed in the small intestine
oral availability
The fraction of drug that reaches thesystemic circulation after oral ingestion.
drug absorption can occur via 4 routes
- Passive diffusion
- Facilitated diffusion
- Primary/secondary active transport
- Pinocytosis
passive diffusion is a common mechanism for
lipophilic drugs and weak acid/bases
example of lipophilic drug
steroids diffuse directly down conc fradient into GI capillaires
- no polar
some drugs are weak acids and bases
can be protonated or unprotonated
when weak acid is protonated
uncharged
think COO-
when bases are deprotonated
uncharged
think NH3+
drugs pass more readily through membrane when
uncharged
- protonated acids can pass
- deprotonated bases can pass
if a drug has a pkA of 5 and the ph of the samll intestine is 6
most of the drug will be deprotonated
—> in weak acids onyl protonated speicies wil pass the membrane
- only 10% lipopholic and can cross the GI epithelial
faciliated diffusion is carried out by
solute carrier transporters (SLC)
SLC transport
Molecules (or solutes) with net ionic + or – charge (charged molecules) within GI pH range can be carried across epithelia
–>Passive process based on electrochemical gradient for molecule
SLCs are either
Organic Anion Transporters (OATs) or Organic Cation Transporters (OCTs)
- highly expressed 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
factors affecting drug absorption
Physiochemical factors
GI physiology
First pass metabolism by GI and liver
Physiochemical factors
- GI length and surface area
- Drug lipophilicy/ pKa (how protonated the drug is at GI pH)
- Density of SLC expression in GI
GI physiology
first pass metabolism
Reduces availability of drug reaching systemic circulation- therefore affects therapeutic potential
where can first pass metabolism occur
in the Gut lumen, walls or liver
first pass metabolism reduces
oral availability
First pass metabolism can occur in the gut wall, portal vein (uncommon) and in the liver.
which enzymes facilitate first pass metbaolism in the luver
Phase 1 and 2 enzymes
phase 1 enzymes
Cytochrome P450s
phase II
conjugating enzymes
bioavailiability
Fraction of a defined dose which reaches its way into a specific body compartment
which is the most common reference compartment used for bioabailability
circulation (CV)
- for CV compartment bioavailability reference IV bolus is used
IV bolus
no physical/ metabolic barriers to overcome
bioavailability equation
stages 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
major factors affecting drug distribution
1) Drug molecule lipophilicity/ hydrophilicity
2) Degree of drug binding to plasma and tissue protein
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
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
types of capillaries
continous
fenestrated
sinsusoid
continous capillaries
very tight gap junctions (BBB)
fenestrated capillaries
less tight intercellular celft
fenestrations
sinusoid capillaries
leaky large synuses
big fenestrations
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
which ar ethe 3 main body comparments
- Plasma
- Interstitial
- Intracellular
Increasing penetration by drug into interstitial and intracellular fluid compartments leads to:
- Decreasing plasma drug concentration
- Increasing Volume of distribution
apaprent volume of distribition
Models grouping of main fluid compartments as through all in one compartment.
- Summarises movement out of plasma à interstitial à intracellular compartment
- Vd value dependent on push/pull factors described
smaller Vd (vol of dist) values
less penetration of interstitial, intracellular fluid compartments
Larger Vd values
greater penetration of interstitial/ intracellular fluid compartmentd
volum of dist (Vd) equation
Vd units
- Vd units:
- Litres (assume standard 70kg body wt)
- Litres/kg (more referenced to individual patient body wt)
what can affect apparent volume of distribution
- Changes in regional blood flow
- Hypoalbunimea (affecting protein binding)
- Marker increase or decrease in body weight
- Drug interactions
- Renal failure
- Drugs narrow therapeutic ration
- Pregnancy
- Paediatrics
- Geriatric
- Cancer patients
- Anaesthetics
