Lecture 19 - Pharmacokinetics 1 Flashcards
What is pharmacokinetics ?
what the body does to a drug
Phamacokinetics has 4 steps…..
drug in :
Absorption
Distribution
Drug out :
Metabolism
Elimination
outline the possible sites of administration
Focal (on the site) - eye,skin,inhale
good - concentrates drug at action site
less systemic absorbtion so less side affects
Systemic - apply system wide
1) enteral (mouth and GI) - Oral (tablet dissolve or liquid-faster), sublingual, rectal
2) Parenteral - subcutaneous, intramuscular, intravenous, inhalation, transdermal
outline oral drug absorption
oral is most convenient - can take tabs at a easy schedule - 1 daily
Majority of absorption into system done in small intestine by GI epithelium
drug can be absorbed by diffusion, facilitated diffusion, pinocytosis, active transport
explain what/how drugs are absorbed by passive diffusion
‒ Common mechanism for lipophilic drugs, weak acids/ bases
Weak acids/bases - protonated/deprotonated species
can diffuse if uncharged
Lipophilic species crosses GI epithelia
4-5 hrs in Small intestine - long time for lots of absorption to happen
explain what/how drugs are absorbed by Facilitated diffusion
Solute Carrier (SLC) Transport
Molecules (solutes) with net ionic + or – charge within GI pH range can be carried across GI epithelia
Passive transport driven by electrochemical gradient on solute
SLCs are either Organic Anion Transporters (OATs) or Organic Cation Transporters (OCTs)
– Large family – widely expressed
– Pharmacokinetically important for drug absorption and elimination
– Highly expressed in GI, hepatic and renal epithelia
explain what/how drugs are absorbed by Secondary active SLC transport
Some SLCs enable drug transport in the GI by secondary active transport
• e.g. renal OATs and OCTs
• Driven by pre-existing electrochemical gradients, e.g. Na+, (not ATP)
• Examples: – Fluoxetine – SSRI antidepressant co-transported with Na+ ion
what are the factors that affect drug absorption ?
Physiochemical factors -
GI SA
Drug liphophilicity/Pka
SLC expression density
GI physiology
Bllod flow - high after eating - more uptake, low when stressed - lower uptake
GI motitly - slow post meal -more uptake - rapid when diarrhoea - less uptake
Food/pH - food can reduce or increase uptake - a low pH may destroy some drugs
what is first pass metabolism ?
the amount drugs that are metabolised when entering the GI tract/liver before reaching the blood stream for bio-availability
‘First pass’ metabolism by GI and liver
– Gut lumen: gut /bacteria enzymes denature some drugs
– Gut wall/liver: some drugs metabolised by two major enzyme groups
• Cytochrome P450s – Phase 1 enzymes
• Conjugating enzymes – Phase 2 enzymes
• High expression of phase 1 and 2 enzymes in liver
• ‘First pass’ metabolism: `reduces drug availability reaching the systemic circulation (affects therapeutic
potential
how can we avoid first pass metabolism ?
use different routes of administration
Parenteral - IV, SC
Rectal
Sublingual
what is the oral bioavliability of a drug ?
what is the graph to demonstrate this, draw it ?
the fraction of a dose of drug that will reaches circulation unchanged
this is dependent on the first pass metabolism and rate of gut absorption
measure Plasma conc of drug against time
F= amount reaching circulation / total drug given (IV)
Foral = AUCoral/AUCiv
AUC - area under curve
F oral value is between 0 and 1 - it is a measure of bioavliablity
this will help us decide how to administer the drug
F is a measure of bioavaliablity
what is drug distribution ? what factors affect it ?
how well the drug distributes - how well drug permeates though capillaries determines how well the drug will spread through the body
charged / uncharged ect
factors that affect it :
Drug Molecule Lipophilicity/ Hydrophilicity
– Largely lipophilic drugs can move freely across membrane bilayers
– Hydrophilic drug transport across membranes dependent on factors affecting absorption
– Capillary permeability
• Drug pKa and local pH
• Presence of OATs and OCTs
Degree of drug binding to plasma and/or tissue proteins
– In circulation many drugs bind to proteins e.g.
• Albumin Globulins
• Lipoproteins – acid glycoproteins
what is the effect of drugs binding to plasma / tissue proteins ?
only free drug molecules bind to target sites
if the drug is bound it reduces the free drug available
the bound drug acts as a reservoir
explain the concept of therapeutic ratio
draw graphs to explain
Maximum tolerated dose/minimum effective dose
LD50/ED50
a large theraputic window is obvs good - penicillin
a small window is not good - warfarin
as less room for error to get desired affect and overdose patient
we need to dose within this window, so each new tablet does not go over max tolerated dose, but remains effective
a fast release drug may exceed toxic concentration straight away - but have a short acting time so loose effect quickly
a slow release drug may have troubles reaching effective window -but stay for a long time so be careful not to overdose
drug molecules are solutes in body fluid compartments
quick revison - how is our bodys water divided again ?
and hence the drug will split between them
TBW - 42 liters
plasma water - 3 liters
exctracellular water (plasma water + interstitial water) - 14 liters
intracellular water - 28 liters
