Pharmacokinetics Flashcards
what are drugs?
exogenous
signalling molecules
what are the 4 main processes in drug therapy?
Absorption
Distribution
Metabolism
Elimination
what is the mnemonic for the 4 processes in drug therapy?
ADME
of the 4 main processes of drug therapy, which two are involved in ‘drug in’?
Absorption
Distribution
of the 4 main processes of drug therapy, which two are involved in ‘drug out’?
Metabolism
Elimination
what are the 2 types of drug administration
enteral
parenteral
what does enteral mean?
Delivery into internal environment of body - GI Tract
- Oral
- Sublingual
- Rectal
what does parenteral mean?
Delivery via all other routes that are not the GI - includes
- Intravenous
- Subcutaneous
- Intramuscular
What is a useful mnemonic to memorise the types of drug administration?
Oi ! It is Sir! Oral Intravenous Intramuscular Transdermal Intranasal Subcutaneous Sublingual Inhalation Rectal
describe the oral route of drug administration
- Oral route - majority of formulations most convenient
- Normally little absorption in stomach
- Drug mixes with chyme enters small intestine
- Constant GI movement - mixing - presenting drug molecules to GI epithelia
what is the typical transit time for the drug through the small intestines?
3-5 hours
what is the pH of small intestines?
weakly acidic 6/7
how can drug be absorped?
Passive Diffusion
Facilitated Diffusion
Primary / Secondary Active Transport
Pinocytosis
describe passive diffusion of drugs
- Common mechanism for lipophilic drugs weak acids/ bases
- Lipophilic drugs e.g. steroids diffuse directly down concentration gradient into GI capillaries. when drug enters the blood, it is immediately removed due to blood flow
describe passive diffusion of weak acids and bases
weak acids become protonated so become neutral so can pass through the membrane.
weak bases become deprotonated and become neutrak so can pass through the membrane
describe the absorption of valproate
Valproate : Anti -Epileptic Drug weak acid pKa = 5
• In gut at pH 6 - 10 % Valproate protonated - Lipophilic
• Lipophilic species crosses GI epithelia
describe facilitated diffusion in drug absorption
Solute Carrier (SLC) Transport • Molecules (or Solutes) with nett ionic + or - charge within GI pH range can be carried across GI epithelia • Passive process based on electrochemical gradient for that (solute) molecule
what are solute carrier transporters?
SLCs are either Organic Anion Transporters and Organic cation Transporters
• Large family – expressed in all body tissues
• Pharmacokinetically important for drug absorption and elimination
• Highly expressed in GI, Hepatic and Renal Epithelia
describe secondary active transport in drug absorption
• SLCs can also enable drug transport in GI by Secondary Active Transport
• Not utilise ATP -Transport driven by pre-existing electrochemical gradient
across GI epithelial membrane e.g. Renal OATs and OCTs
give 2 examples of drugs that are absorbed using secondary active transport
- Fluoxetine/Prozac - SSRI antidepressant co-transported with Na+ ion
- Penicillins - co-transported with H+
ion
what are the Physicochemical Factors that affect drug absorption?
- GI length /SA
- Drug lipophilicity / pKa
- Density of SLC expression in GI
what are the GI Physiology factors that affect drug absorption?
- Blood Flow: Increase post meal – drastically reduce shock/anxiety exercise
- GI Motility: Slow post meal - rapid with severe diarrhoea
- Food /pH: Food can reduce/increase uptake. Low pH destroy some drugs
how does first pass metabolism affect drug absorption?
‘First Pass’ metabolism: Reduces availability of drug reaching systemic circulation - therefore affects therapeutic potential
describe first pass metabolism in gut lumen and gut wall/liver
• Gut Lumen: Gut/Bacterial Enzymes - can denature some drugs
• Gut Wall/Liver: Some drugs metabolised by two major enzyme groups
Cytochrome P450s - Phase I Enzymes
Conjugating - Phase II Enzymes
• Much larger expression of Phase I &II Enzymes in Liver
define bioavailability
Fraction of a defined dose which reaches its way into a specific body compartment
describe bioavailability reference
• CVS (Circulation) is most common reference compartment
• For CVS/Circulatory Compartment
Bioavailability Reference - IV bolus = 100%
- No physical/metabolic barriers to overcome
• For other routes - compare amount reaching CVS by other route referenced
to intravenous bioavailability
• Most common comparison oral or (O)/(IV)
how do you work out oral bioavailability
(F)?
Measure:
• Total Area Under Curve for IV route
• Total Area Under Curve for Oral route
F = Amount reaching Systemic Circulation/ Total drug Given IV
F(Oral) = AUC(Oral)/AUC(IV)
• F lies between 0 and 1
• Informs choice of administration route
what is drug distribution?
How drugs journey through body
• To reach and interact with therapeutic and non-therapeutic target
• Interaction with other molecules - affect on pharmacodynamics
what is the first stage of drug distribution?
- Bulk flow - Large distance via arteries to capillaries
- Diffusion - Capillaries to interstitial fluid to cell membranes to targets
- Barriers to Diffusion - Interactions /local permeability/non- target binding
At the level of the capillary, how is the diffusion process affected by the ‘microleakiness’ of the capillaries?
• Differing levels of capillary permeability
• In certain capillary beds the capillary endothelial cells
can be fenestrated or sinusoidal meaning there are larger gaps for the drugs to diffuse through. For many drug molecules, these ‘leak’ points facilitate access into the interstitial fluid and from there onto the drug targets.
• Variation in entry by charged drugs into tissue interstitial fluid/target site
• Capillary membrane also express endogenous Transporter & OATs/OCTs
what are the 3 types of capillaries?
continuous
fenestrated
sinusoids
how are the structure in the body described?
• In reality body highly heterogenous set of
structures and tissues
• This heterogeneity and the differing proportion of major cellular and molecular types within a tissue, can significantly affect the concentration of drug
achieved throughout the different tissues
• Multiple mini ‘compartments’
what are the Major factors affecting drug distribution?
Drug Molecule Lipophilicity/Hydrophilicity
Degree of drug binding to plasma and/or tissue proteins
The mass or volume of tissue and density of binding sites
within that tissue
how does Drug Molecule Lipophilicity/Hydrophilicity affect drug distribution?
• If drug is largely lipophilic can freely move across membrane barriers
• If drug is largely hydrophilic journey across membrane barriers dependent
on factors described for Absorption
Capillary permeability ( very ‘tight’ to very leaky )
Drug pKa & Local pH
Presence of OATs/OCTs (in capillary and target tissue membranes
how does Degree of drug binding to plasma and/or tissue proteins affect drug distribution?
In circulation many drugs bind to proteins e.g.
Albumin - Globulins
Lipoproteins - Acid glycoproteins
• Only free drug molecule can bind to target site(s) • Binding in plasma/tissue decreases free drug available for binding • Plasma/Tissue protein bound drug acts as ‘dynamic reservoir’
describe the equilibrium between bound and unbound protein
• Binding forces not strong – bound/unbound in equilibrium • Binding for given drug can • be up to 100% (Aspirin 50% ) • Varying number of binding site for given drug • Competition for binding site affects free plasma conc and Pharmacodynamics
how do we make it simpler to think of how drug moves throughout whole body?
Drug Molecules are Solutes in Body Fluid Compartments:
Body Fluid Compartments: A Simple Model for Drug
Distribution in the Human Body
• Simplify body fluid compartments in to model with three main compartments -
- Plasma Water = Plasma Water
- Extracellular Water = Plasma Water + Interstitial Water
- Total Body Water = Plasma Water + Interstitial Water + Intracellular Water
what does Increasing Penetration by Drug into Interstitial and Intracellular Fluid Compartments Lead to?
Decreasing Plasma Drug Concentration
Increasing Vd
what is the‘Apparent’ Volume of Distribution (Vd)?
it is a ratio used to estimkate the distribution of a drug within the body relative to the total amount of fluid in the body.
Models grouping of main fluid compartments as though ‘All One Compartment’
• Hence ‘Apparent’ : it’s a very useful ‘Pretend’ Concept
• Provides summary measure of drug molecule behaviour in distribution
• Referenced to Plasma concentration – easiest to measure
• Summarises movement out of Plasma –> Interstitial
–> Intracellular Compartment
• Vd value dependent on push/pull factors described
what is the equation for the ‘Apparent’ Volume of Distribution (Vd)?
Volume of Distribution (Vd) = Drug Dose/[Plasma Drug]t=0
what does smaller values of Vd mean?
Smaller Vd values - less penetration of Interstitial/Intracellular Fluid Compartment
what does larger values of Vd mean?
Larger Vd
values - greater penetration of Interstitial/Intracellular Fluid Compartment
what are the Vd units?
Litres (assume ‘standard’ 70 kg body wt. )
Litres/kg (more referenced to individual patient body wt. )
what is drug elimination?
Elimination
• Term used to cover both Metabolic and Excretory Processes
• Both ‘flow’ processes closely integrated to optimise drug removal
what 2 functions does drug elimination have?
• Protective and Homeostatic function
what is the evolutionary advantage of drug elimination?
• Evolutionary advantage in recognising xenobiotics – potential toxins
what type of molecules does elimination remove?
• Elimination removes both exogenous and endogenous molecular species
what is drug metabolism?
drug metabolism refers to the conversion of a drug from its active form to an inactive form(can be broken down).
Once metabolised - drugs usually inactivated but not always
where does drug metabolism largely take place and via which enzymes?
Drug Metabolism largely takes place in Liver via Phase 1 and II enzymes
how many phases are there in hepatic metabolism?
Phase 1 and II
where are phase I and phase II enzymes normally found?
found all over the body however the major abundance of these enzymes would be in the liver - Very large hepatic reserve – also ‘first port of call’ after GI absorption
what is the function of phase 1 and phase 2 enzymes in drug metabolism?
Metabolise drugs - increase ionic charge in order to enhance renal elimination.
an example of lipophilic drugs, without being acted on by these enzymes, they’d diffuse out of the renal tubes and back into plasma meaning they won’t be excreted.
which molecule carries out phase 1 metabolism?
Phase 1 Metabolism is carried out by Cytochrome P450 Enzymes
what are Cytochrome P450 Enzymes(CYP450s)?
they are large group of isozymes that you can find on the external side of the ER. They;re versatile generalists which means that they can metabolise a wide range of molecules. However, they carry this process out slowly.
what is the function of Cytochrome P450 Enzymes?
their job is to increase the ionic charge in drugs, they do this through catalysing redox, dealkylation and hydroxylation reactions
what happens to the drugs after they are metabolised by phase 1 enzymes?
they will either be eliminated immediately or will go to phase 2
what are pro-drugs?
they are inactive drugs which become active after being metabolised by phase 1 enzymes.
give an example of a pro drug
an example is codeine which is activated to morphine. codeine is metabolised by the CTYP2D6 enzyme, this enzyme shows genetic polymorphism
which molecules carry out phase 2 metabolism?
Phase 1I Metabolism is carried out by Hepatic Enzymes
what is the difference between hepatic enzymes and CTYP2D6 enzymes?
- Phase I1 enzymes - mainly cytosolic enzymes - not membrane bound like CTYP2D6 enzymes
- Phase II still generalists but exhibit more rapid kinetics than CYP450s
describe phase 2 drug metabolism
- Enhance hydrophilicity by further increasing ionic charge - add to Phase I
- Catalyse: Sulphation - Glucorinadation - Glutathione conjugation - .Methylation and N-acetylation
- Phase II metabolised drugs have further increased ionic charge
- Phase II metabolism enhances renal elimination
describe the Cytochrome P450 Enzymes and give the 5 main isozymes
Cytochrome P450 enzymes include three superfamilies
• Three superfamilies CYP 1, 2 and 3
• Isozyme members in each family coded by suffix: e.g. CYP3A4
• Six isozymes metabolise around 90% prescription drugs. 5 of these are:CYP 1A2, CYP 2C19, CYP 2D6, CYP 2C8/9, CYP 3A4/5
• Other isozymes exhibit very variable hepatic expression
• Each isozyme optimally metabolise specific drugs but do show overlap
what are the factors that affect drug metabolism?
Many Factors of Direct Clinical Relevance
• Age (Variable patterns in paediatric groups reduced in elderly)
• Sex (gender differences drugs e.g. alcohol metabolism slower in women)
• General Health/Dietary/Disease - you need to consider the health of the liver, kidneys and the CVS(HRH)
- negative effects of this causes a Decreased Functional Reserve
CYP450s:
• Other drugs (Rx/OTC) can induce or inhibit CYP450s
• Genetic variability/polymorphism/ non-expression affects CYP450s
what are the Major Categories for Factors
affecting Drug Elimination: The Royal Acronym HRH?
- Heart (CVS)
- Renal
- Hepatic
–>Decreased Functional Reserve
describe CYP450 induction and the therapeutic consequences of this
• Concurrent administration of certain drugs (including just the one drug) can
induce specific CYP450 isozymes
• Induction mechanism via: increased transcription ; increased translation ; slower degradation
• If another drug in body metabolised by induced CYP450 isozyme then its
rate of elimination will be increased
• Plasma levels of drug will then fall
• For patient can have serious therapeutic consequences if levels drop significantly
• Induction process typically occurs over 1-2 weeks
give an Example of a drug that is affect by CYP450 Induction?
Carbamezepine (CBZ)
• CBZ is an anti-epileptic metabolised by CYP3A4
• CBZ induces CYP 3A4 – lowering its own levels affecting control of epilepsy
• CBZ needs careful monitoring in first few month post prescription
describe CYP450 Inhibition
• Concurrent administration of certain drugs (including just the one drug) can
inhibit specific CYP450 isozymes
• Inhibition mechanism via: competitive/non-competitive inhibition
• If another drug in body metabolised by inhibited CYP450 isozyme then its
rate of elimination will be slowed down
• Plasma levels of drug will then increase
• For patient can have serious side effects consequences if levels rise significantly
• Inhibition process occurs within 1 to a few day
give an example of CYP450 Inhibition
Grapefruit Juice
• Grapefruit Juice inhibits CYP 3A4
• CYP 3A4 metabolises Verapimil used to treat high blood pressure (BP)
• Consequence can be much reduced BP and fainting
describe how genetic factors can affect phase 1 drug metabolism and what needs to be considered in relation to this
when it comes to certain CYP450 isozymes, there is genetic variation present that affects who is more likely and unlikely to present it.
for example:
• CYP2C9: Not expressed in: 1% Caucasians; 1% Africans
• Metabolises NSAIDs, Tolbutamide, Phenytoin,
• CYP2C19: Not expressed in: 5% Caucasians; 30% Asians
• Metabolises Omeprazole, Valium, Phenytoin
• Need to consider safety/efficacy if not metabolised /rapidly metabolised
what is Genetic Polymorphism?
the term relates to existence of multiple forms of a gene
describe how genetic polymorphism affects phase 1 drug metabolism
‘Pro-drugs’ activated by Phase I metabolism to active species
Earlier example: Codeine to Morphine
• CYP2D6 gene highly polymorphic
• CYP2D6 variants categorized into: poor; normal/high; ultrarapid metabolisers
Poor - codeine to morphine - may not experience pain relief
Ultrarapid - codeine to morphine - lead to morphine intoxication/ADRs
