Pharmacokinetics Flashcards
What are the four main processes in Drug Therapy?
Absorption (mainly through GI tract) -In
Distribution -In
Metabolism (elimination) -Out
Excretion (elimination) -Out
How can mathematical models be useful?
Mathmatical models are useful in describing, predicting or approximating changes in drug concentration over time throughout the body.
Drugs are..
…Exogenous signalling molecules.
What is enteral drug delivery?
Delivery into internal environment of the body through the GI tract. This can be oral, sublingual or rectal.
What is parenteral drug delivery?
Delivery via all other routes that are not the GI -inc.
Intravenous
Subcutaneous
Intramuscular
What is the mnemonic used to remember the routes of drug administration?
Oral
Intravenous
Intramuscular
Transdermal
Intranasal
Sublingual
Subcutaneous
Inhalation
Rectal
How are drugs absorbed?
Most drugs are taken orally because this is most convenient.
Normally little absorption in stomach (SA is around 0.75m^2)
The drug then mixes with chyme and enters small intestine.
Small intestine is around 6-7m in length by 2.5cm diameter so the total SA for absorption is around 35m. (a LOT larger than the stomach).
There is constant GI movement and mixing which presents different drug molecules to the GI tract.
What is the average transit time for drug absorption in small intestine?
3-5hrs. But can vary from 1-10hrs.
pH of small intestine is also weakly acidic (pH 6-7)
How different mechanisms are used to absorb drugs on a molecular level?
Passive diffusion
Facilitated diffusion
Primary / Secondary Active Transport
Pinocytosis (endocytosis and exocytosis -mostly for very large molecules such as insulin)
What is passive diffusion? What kinds of molecules use this method of transport?
This is the most common way for drugs (especially lipophilic drugs and weak acids/bases) to pass across membranes.
Lipophilic drugs (eg steroid diffuse directly down the conc. gradient into GI capillaries.
Over the transit time of 4-5hrs and a very large SA, ionised species diffuses into GI capillary bed easily.
The non ionised ones will then become protonated (because need to have equilibrium of ionised:not ionised in GI tract) and cross the membrane.
EG Valproate which has pKa of 5 so, in the gut at pH6 10% of the Valpoate will be ionised.
What is facilitated diffusion? What kinds of molecules use this method of transport?
A number of nutrient and signalling molecules with low lipid solubility and a net residual ionic charge cross the GI epithelia in this manner.
This is a passive process given by the electrochemical gradient for that molecule. The molecules travel through solute carrier proteins.
What is secondary active transport? What kinds of molecules use this method of transport?
SLCs can also enable drug transport in GI by secondary Active transport.
This does not use ATP -Transport is instead driven by pre-exisiting electrochemical gradients across the GI epithelial cell membrane.
EG Fluoxetine/Prozac is an SSRI antidepressant that is co-transported with Na+ ion..
What are SLCs? What two categories are they divided into?
Solute Carrier proteins. These are divided into Organic Anion Transporters (OAT) and Organic Cation Transporters (OCT).
Factors Physiochemical affecting drug absorbtion?
GI length and surface area
Drug lipophilicity /pKa
Density of SLC expression in GI
What are the physiological features of the GI tract that affect drug absorption?
Blood flow- This increases post meal and drastically reduces with thick/anxiety and with exercise.
GI motility- This is slow post meal and rapid with severe diarrhoea.
Food / pH: Food can reduce/increase the uptake. Low pH will destroy some drugs.
What other factors affect drug absorption?
First Pass metabolism by GI and Liver.
Gut Lumen : Gut/ Bacterial enzymes can denature some drugs
Gut wall / Liver : Some drugs are metabolised by two major enzyme groups: Cytochrome P450s (phase I enzymes) and Conjugating (Phase II enzymes)
There is a much larger expression of phase I and II enzymes in the liver.
‘First pass” metabolism: reduces availability of drug reaching systemic circulation and therefore affects their therapeutic potential.
What is Bioavailability?
Bioavailability is a fraction of a defined dose which reaches its way into a specified body compartment.
CVS is the most common reference compartment. For CVS/ circulatory compartment, if given using IV there is 100% bioavailability.
How do you work out bioavailability?
Bioavailability = amount of drug reaching systemic circulation / Total amount of drug administered. (no. between 0-1)
a comparison of the bioavailability of the same drug given in different ways (often compare IV to oral) informs the choice of administration route.
Primary way drugs get circulated through the body?
Through the circulatory system.
First stage…
Bulk Flow -Large distance via arteries to capillaries
Diffusion -Capillaries to interstitiel fluid to cell membranes to targets
Barriers to Diffusion -Interactions / local permeability / non-target binding (muscle and adipose)
What barriers are there to diffusion?
-Interactions / local permeability / non-target binding (muscle and adipose)
How are drugs distributed through the body?
Differing levels of capillary permeability enable variation in entry by charged drugs into tissue interstitial fluid and from there into target sites.
The amount of capillaries in different places also allow for variation in distribution. For example, drugs are likely to get to capillary dense tissues such as heart and kidney much faster than to bone and adipose.
What are the major factors affecting drug distribution?
Drug molecule lipophilicity / `Hydrophilicity.
-If a drug is largely lipophilic it can freely move across membrane barriers. Whereas, if a drug is largely hydrophilic the journey across membrane barriers is dependant on factors described for absorption (such as capillary permeability, drug pKa and local pH and the presence of OATs and OCTs).
Degree of drug binding to plasma proteins and/or tissue protein.
-In circulation, many drugs bind to proteins such as albumin, Globulins, Lipoproteins acid and glycoproteins.
The mass or volume of tissue and density of biding sites within that tissue.
What is the simple model of drug movement between body fluid compartments?
Drug molecules are solutes in Body fluid compartments.
This model shows the movement of water between three main compartments: plasma, interstitial and intracellular water.
(Interstitial and Plasma are extracellular water.) This makes movement of solutes much easier to track and assess.
What are the factors that influence speed of absorption?
Capillary Permeability
Drug pKa and local pH
Present of OATs/OCTs
What affects the degree of drug binding to plasma and/or tissue proteins?
Only free drug molecules can bind to target sites.
Binding in plasma/tissue decreases free drug available for binding
Plasma/Tissue protein bound drugs act as a ‘reservoir’
Binding forces are not as strong -The bind and unbind in an equilibrium
Binding CAN be up to 100% (rare).
What is vol of
Plasma water?
Extracellular water (interstitial and plasma)?
Total body water (plasma, interstitial and intracellular water?
3L
14L
42L
What does increasing penetration by drug into interstitial and intracellular compartments lead to?
Decreasing Plasma Drug conc. Increasing Vd (vol of distribution)
What is the apparent volume of distribution (Vd)?
This is a model grouping the main fluid compartments as thought its ‘all one compartment. This makes it an estimate.
It summarises the movement our of plasma into interstitial and then into intracellular compartments.
Why is Vd useful?
Vd is useful because it provides a summary measure of drug molecule behaviour in distribution. It is referenced to plasma concentration because this is easiest to measure.
Vol of distribution calc? What do the values means?
Vd= Drug dose / conc, plasma drug at time zero.
(in L (If assume 70kg) or L/Kg)
Smaller Vd = less penetration of interstitial/ intracellular fluid compartments.
Larger Vd = greater penetration of interstitial / intracellular fluid compartments.
What can affect the Vd?
Changes in regional blood flow Hypoalbuminea Changes in body weight Drug interactions Renal Failure Drugs with narrow therapeutic ratio Pregnancy Paeds Geriatrics (metabolise drugs differently) Cancer patients Anaesthetics.
What is Elimination?
This is the term used to cover both metabolic and excretory processes
Both ‘flow’ processes closely integrates to optimise drug removal. (particularly between the liver and the kidneys)
Elimination removed both exogenous and endogenous molecular species.
There is a big evolutionary advantage to humans recognising xenobiotics because these could be potential toxins.
It has protective (remove toxins) and Homeostatic (reduce level of endogenous molecules) functions.
What is the role of metabolism in drug elimination?
It increases the ionic charge on drug molecules so it is easier the the kidneys to excrete.
Where does drug metabolism occur?
In the Liver via phase I and II enzymes.
What are phase I and II enzymes?
They metabolise drugs by increasing the ionic charge to enhance renal elimination.
Lipophilic drugs diffuse out renal tubules and back into plasma
Once metabolised, drug usually inactivated.
What happens in
phase I of drug metabolism?
Phase I metabolism is carrier out by cytochrome P450 enzymes. (refered to as CTP450)
This is a large group of over 50 isoenzymes which are located on external face of the ER
They are versatile generalists -They metabolise a wide range of molecules.
after being metabolised, drugs have an increased ionic charge and they are either eliminated directly or go into phase II.
Some ‘pro-drugs’ are activated by phase I metabolism to become active species.
What reactions do phase I enzymes catalyse?
Redox, Dealkylation, Hydroxylation.
Give an example of ‘activating’ a pro drug using phase I enzymes.
Codeine is metabolised to morphine by phase I metabolism.
1 mol of morphine is as competitive as 200 moles of codeine.
It is metabolised by CYP2D6 which exhibits genetic polymorphism. (This means it is different in different people so, different people have different tolerances to codeine.)
What happens during phase II of drug metabolism?
Phase II metabolism is carried out by hepatic enzymes. These enzymes are mainly systolic.
Phase II enzymes are still generalists but then exhibit more rapid kinetics than the CYP450s.
They enhance hydrophilicity by further increasing ionic charge (which adds to the ionic charge added in phase I).
Phase II metabolism enhances renal elimination.
What types of reactions do phase II enzymes catalyse?
Any reaction that adds big molecules to increase charge.
Sulphation, glucorinadation, glutathione conjugation, methylation, N-acetylation.
How many superfamilies of Cytochrome P450 are there? How do you know what enzymes belong to which family?
There are three superfamilies: CYP 1,2 and 3
Isosyme members in each family are coded by a suffix.
How many isozymes metabolise 90% of drugs?
Isozymes are each of two or more enzymes with identical function but different structure.
Six isozymes metabolise around 90% of prescription drugs. (in future, will be able to order genetic tests to see what drugs work)
Other isozymes exhibit very variable hepatic expression.
Each isozyme optimally metabolises specific drugs but do show overlap.
What factors affect drug metabolism?
Age (variable patterns in paediatric groups, reduced in the elderly)
Sex (gender differences in drugs eg alcohol metabolism is slower in women)
General health/dietary/disease -especially Hepatic Renal CVS
Explain CYP450 Induction in phase I metabolism.
Concurrent administration of certain drugs (inc just the one drug) can induce specific CYP450 isozymes.
Induction mechanisms via: increased transcription and translation and decreased degradation.
If another drug in the body is metabolised by induced CYP450 isozymes then its rate of elimination will be decreased.
Plasma levels of the drug will the fall. For a patient, this can have serious therapeutic consequences if levels drop significant,
Induction processes typically occur over 1-2 weeks.
Give an example if CYP450 Induction
Carbamezapine (CBZ) is an anti-epileptic drug which is metabolised by CYP3A4.
CBZ induces CYP3A4 by lowering its own levels affecting the control of epilepsy.
CBZ needs careful monitoring in the first few months post prescription to ensure a safe, therapeutic dose is being given.
Explain CYP450 inhibition in phase I metabolism.
Concurrent administration of certain drugs (inc. just one drug) can inhibit specific CYP450 isoenzymes.
These inhibitory mechanisms can be competitive or non-competitive.
If another drug in the body is metabolised by inhibited CYP450 isozymes then its rate of elimination will be slowed down.
Plasma levels of the drug will the increase. For patients, this can have serious side effects if the levels rise significantly.
The inhibition process occurs within one to s few days.
Give an example of phase I CYP450 Inhibition.
Grapefruit Juice.
Grapefruit juice inhibits CYP3A4.
CYP3A4 metabolises Verapimil which is used to treat high blood pressure. So, having grapefruit juice can lead to reallyyy reduced BP and fainting.
Why is genetic variation in CYP450s important to be aware of?
Need to consider safety / efficacy if not metabolised or rapidly metabolised.
How does CYP2C9 show genetic variation?
Not expressed in 1% caucasians and 1% of africans.
It metabolises NSAIDs, Tolbutamide, Phenatoin.
This means cannot metabolise these drugs.
How does CYP2C19 show genetic variation?
Not expressed in 5% of Caucasians and 30% of Asians.
Metabolises omeprazole, valium and phenytoin so, if this is not expressed then there drugs may not work on these patients.
Why is the polymorphism of CYP2D6 significant?
CYP2D6 gene is highly polymorphic but, it is how codeine gets metabolised.
CYP2D6 variants are categorised into poor. normal/high, ultra rapid metabolisers.
Poor codeine to morphine metabolisers may not experience pain relief.
Ultrarapid rapid metabolisers of codeine to morphine could lead to morphine intoxication / Adverse drug reactions
How does CYP2D6 show genetic variation?
CYP2D6: not expressed in 7% Hyperactive (polymorphism) 30% East Africans.
It metabolises codeine and Tricyclic antidepressants (TCAs).
What is the main route of drug elimination?
Main route of drug elimination is kidney
Other routes inc bile, lung, breast milk (deliver to baby), sweat, tears, genital secretions, saliva.
Be aware that adverse reactions to baby
What are the three processes of elimination through the kidney?
Glomerilar Filtration
Active tubular secretion
Passive tubular reabsorption
Describe the process of renal elimination. (What occurs in each of the three steps..)
Firstly, the free drug enters the bowman proximal tubule via the bowmans capsule. This is GLOMERULAR FILTRATION.
Next, PROXIMAL TUBULAR SECRETION occurs. This is when there is active secretion of drugs. So, OATs and OCTs actively transport ionised molecules (drugs) into the proximal tubule. This causes water to also be reabsorbed. This increases the concentration of solutes so that lipophilics pass black into the blood.
Lastly, DISTAL TUBULAR REABSORPTION occurs. As water is resorbed along the length of the tubule, drug metabolite concentration increases. If this is in a lipophilic form, then it will pass out back into the bloodstream being reabsorbed passively as it goes back down its concentration gradient resulting in a lower rate of effective elimination
What is clearance?
Clearance is defined as the rate of elimination of a drug from the body.
Total drug clearance consists of that from all routes -for most drugs.
Total body clearance = Hepatic clearance +r Renal Clearance.
Define Clearance
“The volume of Plasma that is completely cleared of the drug per unit time.”
Measures in ml/min
Why is clearance clinically useful?
Along with Vd, clearance predicts how long drugs will stay in the body.
It is clinically essential for informing:
-Designing dosing schedule
-Therapeutic regime levels
-Minimising ADRs (adverse drug reactions).
Together why Vd, it provides an estimate to drug half life and it answers the question “How log is the drug in the bod and us it doing any good?”
What is drug half life?
The amount of time over which the concentration of a drug in plasma decreases to one half of that (concentration value it has when it was first measured).
What dependant on?
It is mathematically dependant on Vd and CL
If CL stays the sane and Vd increases then the half life also increases.
If CL increases and Vd stays the same then the half like will decrease.
What can half lives tell us?
Hw long therapeutic effect will last
How much of the drug is left in body so how much is needed in subsequent doses.
6 half lives = no drug in the body.
How do you make a half life graph linear?
Logs!
