Week 6 - An Intractable Problem Flashcards
What is pharmacodynamics?
The effect of the drug on the body
e.g. What are the changes in the body after taking this drug? (lower BP)
What is the definition of absorption as part of ADME?
Process by which drug moves from its site of administration to the systemic circulation
Via:
- Passive diffusion
Lipophilic drugs: cross membrane ‘transcellular’
Hydrophilic drugs: Low molecular weight hydrophilic drugs, pores and gap junctions
- Active transport (large molecular weight drugs, ATP-dependent transporter)
What is pharmacokinetics?
The effect of the body on the drug
e.g. How does body respond to the drug? ADME
List FOUR pieces of information which are found on a medical license
2 marks
The licence for a medicine includes information such as: (Any for ½ mark each)
· What health condition it should be used to treat
· What dose should be used
· What form it takes – such as a tablet or liquid
· Who can use the medicine – for example, only people above a certain age
· How long treatment with that medicine should last
· Warnings about known safety issues – such as side effects and interactions with other medicines
· How the medicine should be stored
When the medicine expires
Explain why the binding of a competitive antagonist to a receptor is a reversible process?
2 marks
A competitive antagonist binds to the same binding site as an agonist. (1/2 mark)
If the concentration of agonist is increased it will replace the binding of the antagonist (1/2 mark) and this will lead to a full tissue response (1/2 mark).
Hence, the antagonism is said to be reversible (1/2 mark).
What is the main route for oral drug absorption?
Passive diffusion via the transcellular pathway
This occurs through enterocytes (simple columnar epithelial cells)
Define the term ‘therapeutic window’.
1 mark
The therapeutic window is the range of drug doses (or drug concentration in the plasma) that produces a therapeutic response without causing significant adverse response (side effects) in the patient.
What is the journey of a drug through the body?
Drug at site of administration
- ABSORPTION -
Drug in plasma
- DISTRIBUTION -
Drug at target organs/tissues
- METABOLISM -
Metabolites in tissues
- ELIMINATION -
Drug or metabolites in urine/faeces
Name the cell type involved in the transcellular pathway which allows oral drugs to be absorbed across the intestine (1/2 mark) AND name one type of membrane transport system in this pathway. [1/2mark]
1 mark
Enterocytes or absorptive cells (1/2 mark)
Any one of the following:
Simple (passive) diffusion
OR carrier-mediated transport
OR active transport (1/2 mark).
What proteins can a drug interact with?
Receptor
Ion channel
Enzyme
Carrier molecule
What are the different types of receptors?
Ligand-gated channels
GPCRs
Enzyme-linked receptors
Intracellular receptors
What is the definition of distribution under ADME?
The reversible transfer of a drug to and from the systemic circulation
The drug has to be unbound (not bound to plasma proteins)
What do drugs bind to?
Proteins in the blood plasma like human serum albumin, lipoproteins, glycoproteins, alpha, beta and gamma globulins
Only unbound drugs can be distributed, metabolised or excreted
What percentage of a drug is usually unbound to plasma proteins?
10%
What is the definition of metabolism in ADME?
Any chemical alteration of a drug by the living system to enhance water solubility and hence excretion
What is the definition of excretion of metabolism in ADME?
The irreversible transfer of a drug from the systemic circulation
Besides binding to its target, what other properties must an oral drug have in order to exert its maximum effect in the body?
Dissolve
Survive a range of pHs (1.5 - 8.0)
Survive intestinal bacteria
Survive liver metabolism
Partition into target organ (get to the receptors where it is needed)
Cross membranes
Avoid excretion by kidneys
Avoid active transport to bile
Avoid partition to non-target organ (in undesired places e.g. brain or foetus)
What happens in the Pre-Clinical Testing of a drug?
How long does this usually last?
Use cells and tissues in culture to test the general effects of the drug (in at least 2 species)
Tests for any potentially life-threatening, deleterious effects
Lasts on average 18 months
What happens Phase 0 of clinical trials?
First time the drug is given to humans (a small group of 10 healthy individuals)
First time pharmacodynamics and pharmacokinetics can be observed in vivo
Checks for any harmful, unforeseeable side effects of the trialed drug
What happens in Phase I of the Clinical Trial?
Still healthy volunteers
Higher cohort
Dose escalation study is implemented to determine the appropriate dosage required to produce the desired effect
What happens in Phase II of a Clinical Trial?
First time actual patients with the condition the drug is supposed to be for are involved
Few hundred participants are given placebo or actual drug
Assess the effectiveness of the new drug by subtracting the placebo’s efficacy from trialled drug
What happens in Phase III of a clinical trail?
Similar to phase II
Several thousands of patients
Increases the reliability of the data
Benefits of the new drug are weighed against side effects
What occurs in Phase 4 of the drug trailing process?
Continous testing and review of the effects of the drug as it is being marketed and sold to the public
Patients can feedback about the effects of the drug to appropriate bodies through the yellow card scheme put in place by the MHRA
What is the MHRA?
Medicines and Healthcare Products Regulatory Agency (MHRA)
The government body that approves and regulates drugs used in healthcare in the UK
Yellow card scheme allows patients to report problems with a drug after it is on the market
How long is a patent in the UK?
20 years
Can be extended for another 5 years
How long does it take for a drug to come to market?
12.5 years
How much does it take for a drug to come to market?
£1,150 million
What is a drug patent?
When one company are the only company to make a drug and charge quite high prices for it
Generic versions of a drug then can be made when a patent has ended, they are a lot cheaper
Give an example of a receptor that is a drug target
Receptor
e.g. intracellular oestrogen receptor (Tamoxifen)
Give an example of an ion channel that is a drug target
Na+ ion channels (Analgesics)
Give an example of an enzyme that is a drug target
Bacterial topoisomerases (Quinolones - antibiotics)
Give an example of a carrier molecule that is a drug target
Na+ K+ 2Cl- symporter (Loop diuretics)
Where does excretion usually take place? (ADME)
Occurs primarily from the kidneys
Give an example of a ligand gated ion channel
Nicotinic acetylcholine receptors
Give an example of G protein coupled receptors
Muscarinic acetylcholine receptors
Give an example of enzyme-linked receptors
HER2
Tyrosine Kinase Receptors
Give an example of intracellular receptors
Oestrogen receptor
How do ligand gated ion channels work?
Activated and then sodium ions etc go through
How do G protein coupled receptors work?
Target binds
G protein is recruited (alpha, beta and gamma subunit)
GDP changed to GTP
The alpha subunit gets phosphorylated and detaches
The phosphorylated alpha subunit then interacts with a downstream protein (e.g. cAMP)
Creates downstream signalling cascades and
2nd Messengers e.g. opening ion channel
GTP is then hydrolysed back to GDP and the signal stops (the alpha subunit binds to GDP and switches the signal off)
What is the affinity of a drug?
How strongly a drug binds to its target
How do intracellular receptors work?
Also known as nuclear receptors
Transport to the nucleus and activates transcription and translation signals
What is the efficacy of a drug?
The ability of a drug to have its ideal effect in ideal conditions (e.g. randomised control trials)
‘The maximum response achievable from a pharmaceutical drug in research settings and to the capacity for sufficient therapeutic effect or beneficial change in clinical settings’
What do agonists do?
Bind and activates receptors
Usually neurotransmitters/ hormones
Useful when there is not enough signal
What is a full agonist?
Produces the maximal possible signal
What is a partial agonist?
Produces a less than maximal signal
What is an antagonist?
Something that blocks receptor activation
Has affinity but no efficacy
Blocks the effects of neurotransmitters/ hormones
Useful when there is too much signal
What is a competitive antagonist?
Competes for binding site
What is a non-competitive antagonist?
Blocks effect through a different binding site (allosteric), different mechanism (physiological), direct interaction with drug molecule (chemical)
Describe the activation of a GPCR
In the resting state, the GPCR is linked to an enzyme called a G protein
When a ligand binds to a G-protein coupled receptor, the G protein is activated and GDP is converted to GTP
This in turn activates downstream signals
The G protein is switched off by the hydrolysis of GTP to GDP
How exactly does Tegaserod increase peristalsis in the colon?
5-HT4 receptor is found in the colon and its activation by Tegaserod stimulates release of neurotransmitters involved in peristalsis which are Acetylcholine and nitric oxide
This increases the rate of peristalsis
This decreases visceral sensitivity and reduces pain
What is an inverse agonist?
Decreases the ongoing level of signal
What 2 neurotransmitters are involved in peristalsis? What receptor is activated to release them?
Acetylcholine
Nitric oxide
5-HT4 receptor
What is the action of tubocurarine?
Antagonist
Muscle relaxant for surgery
Working on ligand-gated sodium channels
What is the action of atropine?
Antagonist
Inhibits the parasympathetic nervous system - decreases heart rate and saliva
Works on G Protein Coupled Receptors
What is the action of FP-1039?
Antagonist
Cancer therapy (development)
Works on tyrosine kinase
What is the action of Tamoxifen?
Antagonist
Breast cancer treatment
Works on nuclear receptors, oestrogen receptor
Where are G-protein coupled receptors found?
They are found with the membrane
Transmembrane regions
What neurotransmitters activate G-protein coupled receptors?
Acetylcholine
Serotonin
Noradrenaline
Hormones
What percentage of human drug targets are G-protein coupled receptors?
27%
What type of receptor is the 5-HT 4 receptor?
GPCR
What are G proteins made up of?
An alpha, beta and gamma subunit
Which subunit of a G protein detaches?
Alpha
What is 5-HT4 receptor also known as?
Serotonin type 4 receptor (UK)
5 Hydroxy-tryptonine receptor (USA)
Is Tegaserod an agonist or antagonist? What type?
Where is its receptor found?
Partial agonist
High affinity
5-HT4 receptor is found in the colon
Which part of the body is pharmacokinetics and ADME and which part of the body is pharmacodynamics in?
ADME and Pharmokinetics are at the same time when the drug enters and body tries to metabolise and excrete it etc
You see how much concentration is left in the plasma
Pharmacodynamics is from the plasma into the site of action, and you see the effect of the drug on the body and the concentration that is left at the site of action that is actually necessary
At the site of action, what 2 things does the drug need to be in order for it to be clinically useful?
In sufficient quantity
For suitable duration
How does ADME influence drug design?
How much of a dose is needed is effect by:
- How quickly it gets to the site of action
- How soluble the drug is
- Avoiding overdose
- How quickly it metabolises
What nerves do you have in the GI tract?
Inside the GI tract you have the enteric nervous system inside the wall localised primarily in the myenteric plexus and submucosal plexus
You also have the autonomic nervous system with sympathetic (‘fight or flight’) and parasympathetic (‘rest or digest’)
Sympathetic: Heart rate and breathing rate increases, blood directed away from ‘non essentials - i.e. the gut’ and moves towards the heart and muscles for fast action - inhibits digestion
Parasympathetic: Relaxed, gastrointestinal secretion and motility increase
The enteric nervous system has parasympathetic and sympathetic inputs and can work independently of them too
What are the two main plexuses of the enteric nervous system?
Submucosal (Meissner’s)
Myenteric (Auerbach’s)
What exactly is the enteric nervous system?
The enteric nervous is the peripheral extension of the autonomic nervous system that is capable of some independent function
It has both sympathetic and parasympathetic inputs
When was the enteric nervous system established as a separate functional part of the nervous system?
1970s
How does the parasympathetic stimulation promote what it does?
Vagal stimulation increases the tone of the intestinal wall and increases the rate of peristalsis
Increases digestion and absorption
How does the sympathetic stimulation cause what it does?
Reduces peristalsis and tone but does not abolish them
Also increases tone in several sphincters delaying movement of gut contents
When does peristalsis cease?
Only if the submucosal and myenteric plexuses in the gut wall are paralysed
Peristalsis continues even if all the nerves to the gut are cut (parasympathetic or sympathetic)
What is the primary neurotransmitter in the enteric nervous system?
Acetylcholine
What are the different neurotransmitters in the enteric nervous system?
Acetylcholine Noradrenaline GABA Nitric oxide Serotonin
What do the peripheral autonomic nervous pathways contain?
Pre-ganglionic and post-ganglionic neurons
What is the small intestine made of?
Duodenum
Jejunum
Ileum
What is the large intestine made of?
Cecum (pouch)
Colon (ascending, transverse, descending)
Rectum
What muscles are involved in peristalsis?
Longitudinal and circular muscles
How do drugs usually cross membranes in oral absorption?
Passive diffusion of lipophilic drugs through the membrane - transcellular pathway (main route for most oral drugs)
Passive diffusion of hydrophilic drugs, through pores and gap junctions between the cells (paracellular, there are usually water channels in between cells)
Low molecular weight
Also have active transport of large molecules by transport proteins (e.g. glucose and amino acids)
Requires energy.
What determines the speed at which a drug crosses membranes?
Size of the drug
Lipophilicity of the drug (physiochemical properties)
What does transcellular pathway mean?
Through the membrane
What does paracellular pathway mean?
Junctions between the cells (water channels, pores, gap junctions)
What is the function of goblet cells?
Secreting mucus
What factors affect absorption?
Acid stability - stable in acidic stomach conditions (pH1) and then absorb in neutral small intestine conditions (ph7)
Solubility - drug requires sufficient aqueous solubility for dissolution (can only absorb something that is dissolved)
Permeability - poor permeability, gut wall metabolism/efflux can lead to poor absorption across the intestinal wall (disease, ulcers can affect this)
Lipophilicity - if goes through cell wall needs to be lipophilic enough but polar enough to be sufficiently water soluble
What is the main plasma protein that drugs bind to?
Albumin
What is the route for the drug to take?
In ABSORPTION Blood DISTRIBUTION Tissues
What drugs can be distributed?
Unbound drugs
Unbound to plasma proteins
What percentage of the drug usually binds to plasma proteins?
98%
What percentage of the drug is free for binding to the target?
2%
How does the blood from the stomach, small intestine and large intestine get to the liver?
Hepatic portal vein
What is Phase I (first pass metabolism)?
When new polar groups on the drug are added on by oxidation, reduction and hydrolysis reactions
This is so the drug would be more polar and water soluble to then be more easily degraded and excreted
Makes Phase II reactions more likely
What family of enzymes undertakes oxidation in Phase I metabolism?
Cytochrome p450
What types of drugs usually undergo Phase I metabolism?
Warfarin Anti-depressants Anti-epileptics Statins Codine
What happens in Phase II metabolism?
The drug becomes larger, more polar, more water soluble
One of the following molecules are added on: ‘conjugated’
- glutathione
- sulphate
- glucornide
Makes it more likely for the drug to be excreted by the kidneys and eliminated
Hepatic and renal checks are often done before giving patients drugs
What molecules are added in Phase II metabolism?
- glutathione
- sulphate
- glucornide
What types of reactions happen in Phase I metabolism?
Hydrolysis
Oxidation
What types of reactions happen in Phase I metabolism?
Conjugation
What are the main points around Renal Excretion?
- all unbound drug in plasma is filtered in the glomerulus (very polar compounds only)
- some compounds are actively secreted into the urine along the proximal tube
- unionised drug can undergo passive reabsorption from urine into blood along the length of nephron (so net excretion is zero - important to note in dosing)
- drug that is bound to plasma proteins is not filtered
What is the PKPD relationship?
Define each and then state how they work together
Pharmacokinetics - the effect of the body on the drug
Pharmodynamics - the effect of the drug on the body
Relationship:
The potential for the drug to have its desired effect (PD) before the drug is metabolised and eliminated from the body (PK)
Understanding this helps with figuring out doses, frequencies etc
What are factors that can affect the PKPD ?
Clinical status
Nutritional status
Co-administration of two or more drugs
Gender
Weight
Patient’s age
What is the concentration that is required for a drug to work called?
Minimum effective concentration (MEC)
What is the concentration that may caused side effects/toxicity called?
Maximum tolerated concentration (MTC)
What does a standard plasma concentration/time profile look like?
See graph in powerpoint
Draw out
Explain why the plasma concentration of a drug/time profile has the curve it does?
Essentially ADME
The drug is absorbed and enters the blood stream, concentration rises
Compound distributes into tissues and absorption rates start to slow down
Drug is metabolised and excreted from the systemic circulation
In principle, how does the body see drugs?
It sees it as toxic and foreign
So it will try and eliminate it asap
What is the steady state concentration?
In the PKPD relationships and looking at the plasma concentration/time profiles
Steady state concentration is basically when the drug concentrations is starting to drop, you time your dosing and give the patient another dose, to boast the drug concentration a little bit to make it stay in the therapeutic window
What is the therapeutic window?
The range of drug doses (or drug concentration in the plasma) that produces a therapeutic effect
What are the different stages of the drug discovery process?
Target selection (condition/ disease/ target chosen)
Target validation (is the target the right target, if inhibited/activated does it do what you want it to do?)
Load discovery (High throughput screening to find what compounds interacts with the target)
Load optimisation (several molecules are chosen, drug is optimised, chemists will change the chemistry of the drug to make it have higher or lower affinity for the receptor, more acidic/basic)
Preclinical development (will it kill you? in vitro and in vivo models)
Clinical development (side effects)
Regulatory approval (convince others)
When do patents begin?
Right at the beginning of the process at target selection
So will have 20 year patents, and 5 years left of their patent to make their money back
What fraction of compounds entering preclinical development?
1/13 compounds
How many compounds enter the Drug Discovery stage?
10,000
How many compounds enter Pre-clinical trials?
250
What type of cells are enterocytes?
Simple columnar epithelial cells
How many compounds enter clinical trials?
5
How many drugs are FDA review?
1
When was the Medicines and Healthcare Regulatory products Agency (MHRA) formed?
2003?
What is the function of the MHRA?
Regulation of clinical trials
Assessment and authorisation of medicinal products in the UK
Operates post-marketing drug surveillance
When was the EMA formed?
1993
What does the EMA stand for?
European Medicines Agency
What does MHRA stand for?
Medicines and Healthcare Regulatory products Agency
What are the functions of the EMA?
Coordinates the evaluation and supervision of the new medicinal products
Grants opinion on licensing and oversees pharmacovigilance
(Pharmaceuticals as well as medical devices)
What does FDA stand for?
Food and Drug Administration
In the US
When was the FDA established?
1927
What are the functions of the FDA?
Responsible for regulation and supervision of drug safety
Drug assessment, authorisation, post-marketing surveillance
Who can report concerns about medicines and devices with the Yellow Card Scheme?
Healthcare professionals and the general public
What can you report with the Yellow Card Scheme?
- Side effects (adverse drug reactions or ADRs)
- Medical devices adverse incidents
- Defective medicines of poor quality
- Counterfeit or fake medicines or medical devices
- Safety concerns for e-cigarettes or their refill containers (e-liquid)
What membranes might a drug have to cross if orally absorbed?
Enterocytes in the GI tract
Epithelial cells that line the tissues/organs
Explain the basics of clinical trials
Phase 0 - Lab to human
Phase I - Small group of healthy volunteers, evaluate safety of the new treatment (10s)
Phase II - Larger group and in people with condition being targeted (100s) (efficacy, renal function, hepatic function, cardiac problems)
Phase III - Larger scale (1000s) (dosage, effects on different populations, toxicity, double blind, match patients for disease, age sex etc)
Phase IV - Post marketing, adverse reaction reports
What is a double blind clinical trial?
Scientists and patients don’t know if they are taken the drug or control/ current treatment
Why is a double blind clinical trials important
Biased
What is the new drug that has replaced Tegaserod?
5 HT-4 receptor agonist called prucalopride (Shire Pharmaceuticals) approved for use in Europe for constipation in females
EMA approved this compound after extensive demonstration of cardiac safety
Not many of these drugs on the market at all
Where does peristalsis happen?
Oesophagus
Stomach
Intestines
Why was Tegaserod taken off the market?
Withdrawn for increased risk of heart complications
Tachycardias and arrhythmias
How is Tegaserod linked to the heart?
The 5-HT4 receptor in the colon is its main target
There are similar receptors in the heart, causing increased contractions
What is intractable constipation?
Constipation that is prolonged and does not resolve with the usual therapeutic measures
What type of receptor is a 5-HT4 receptor?
G Protein Coupled Receptor
What is Tegaserod?
Selective partial agonist that binds with high affinity to 5-HT4 receptors in the colon
Stimulates the peristaltic reflex and intestinal secretion
Thus promoting gastric emptying and prevents constipation
What is Tegaserod?
A 5-HT4 agonist used for the management of IBS and constipation
How does Tegaserod increase peristalsis?
5-HT4 receptors
These receptors are located in the colon on motor nerves
When the 5-HT4 receptors are activated, they facilitate release of transmitters involved in peristalsis (ACh and NO)
This increases the rate of peristalsis
Also decreases the colon’s sensitivity and reduces the pain
