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
what are the conscequences of a drug having increasing penetration into interstitial and intracellular fluid compartments
a decreasing palsma drug concentration
an increasing volume of distribution -Vd
what is Vd ?
how would one find Vd on some graphs
Apparent Volume of distribution (Vd)
- Theoretical volume into which drug is distributed if this occurred instantaneously
- Provides a summary measure of drug molecular behaviour in distribution
- Referenced to plasma concentration and dose
- Obtained by extrapolation of plasma levels to zero time - assume drug conc at t0 if we obtain distribution instantly
Vd = total amount of drug in body (dose) / plasma drug conc at t0
measures in Liters/kg or liters and assume standard 70kg man
what do smaller and larger Vd values represent ?
Smaller Vd values – low penetration of interstitial/ intracellular fluid compartments and fat
stays in blood palsma
highly charged hydrophillic molecules
• Larger Vd values – greater penetration of interstitial/ intracellular fluid compartments and fat
does not stay in plamsa
example - highly liphophillic uncharged molecules
what affects Vd values ?
many things !
cancer, preganancy, geriatrics ect
what are class I and class II drugs
Protein Binding interactions are important when it Is highly bound to albumin (>90%)
Class I /object drug - used at a dose lower than number of albumin binding sites - as will exist as free drug alot - not fully bound to albumin
Class II / precipitant drug - used at doses greater than the albumin binding site number
it is highly protein bound - need to overload to give free drug availability
due to a higher affinity for albumin class II drugs will displace class I drugs - be careful as we may all of a sudden have more of the drug than we expect !
example - class 1 warfrin will be displaced by class II asprin
