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Week 6 - An Intractable Problem Flashcards

1
Q

What is pharmacodynamics?

A

The effect of the drug on the body

e.g. What are the changes in the body after taking this drug? (lower BP)

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2
Q

What is the definition of absorption as part of ADME?

A

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)
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3
Q

What is pharmacokinetics?

A

The effect of the body on the drug

e.g. How does body respond to the drug? ADME

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4
Q

List FOUR pieces of information which are found on a medical license

2 marks

A

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

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5
Q

Explain why the binding of a competitive antagonist to a receptor is a reversible process?

2 marks

A

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).

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6
Q

What is the main route for oral drug absorption?

A

Passive diffusion via the transcellular pathway

This occurs through enterocytes (simple columnar epithelial cells)

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7
Q

Define the term ‘therapeutic window’.

1 mark

A

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.

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8
Q

What is the journey of a drug through the body?

A

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

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9
Q

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

A

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).

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10
Q

What proteins can a drug interact with?

A

Receptor
Ion channel
Enzyme
Carrier molecule

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11
Q

What are the different types of receptors?

A

Ligand-gated channels
GPCRs
Enzyme-linked receptors
Intracellular receptors

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12
Q

What is the definition of distribution under ADME?

A

The reversible transfer of a drug to and from the systemic circulation

The drug has to be unbound (not bound to plasma proteins)

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13
Q

What do drugs bind to?

A

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

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14
Q

What percentage of a drug is usually unbound to plasma proteins?

A

10%

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15
Q

What is the definition of metabolism in ADME?

A

Any chemical alteration of a drug by the living system to enhance water solubility and hence excretion

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16
Q

What is the definition of excretion of metabolism in ADME?

A

The irreversible transfer of a drug from the systemic circulation

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17
Q

Besides binding to its target, what other properties must an oral drug have in order to exert its maximum effect in the body?

A

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)

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18
Q

What happens in the Pre-Clinical Testing of a drug?

How long does this usually last?

A

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

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19
Q

What happens Phase 0 of clinical trials?

A

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

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20
Q

What happens in Phase I of the Clinical Trial?

A

Still healthy volunteers
Higher cohort

Dose escalation study is implemented to determine the appropriate dosage required to produce the desired effect

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21
Q

What happens in Phase II of a Clinical Trial?

A

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

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22
Q

What happens in Phase III of a clinical trail?

A

Similar to phase II

Several thousands of patients

Increases the reliability of the data

Benefits of the new drug are weighed against side effects

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23
Q

What occurs in Phase 4 of the drug trailing process?

A

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

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24
Q

What is the MHRA?

A

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

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25
How long is a patent in the UK?
20 years | Can be extended for another 5 years
26
How long does it take for a drug to come to market?
12.5 years
27
How much does it take for a drug to come to market?
£1,150 million
28
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
29
Give an example of a receptor that is a drug target
Receptor e.g. intracellular oestrogen receptor (Tamoxifen)
30
Give an example of an ion channel that is a drug target
Na+ ion channels (Analgesics)
31
Give an example of an enzyme that is a drug target
Bacterial topoisomerases (Quinolones - antibiotics)
32
Give an example of a carrier molecule that is a drug target
Na+ K+ 2Cl- symporter (Loop diuretics)
33
Where does excretion usually take place? (ADME)
Occurs primarily from the kidneys
34
Give an example of a ligand gated ion channel
Nicotinic acetylcholine receptors
35
Give an example of G protein coupled receptors
Muscarinic acetylcholine receptors
36
Give an example of enzyme-linked receptors
HER2 Tyrosine Kinase Receptors
37
Give an example of intracellular receptors
Oestrogen receptor
38
How do ligand gated ion channels work?
Activated and then sodium ions etc go through
39
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)
40
What is the affinity of a drug?
How strongly a drug binds to its target
41
How do intracellular receptors work?
Also known as nuclear receptors Transport to the nucleus and activates transcription and translation signals
42
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'
43
What do agonists do?
Bind and activates receptors Usually neurotransmitters/ hormones Useful when there is not enough signal
44
What is a full agonist?
Produces the maximal possible signal
45
What is a partial agonist?
Produces a less than maximal signal
46
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
47
What is a competitive antagonist?
Competes for binding site
48
What is a non-competitive antagonist?
Blocks effect through a different binding site (allosteric), different mechanism (physiological), direct interaction with drug molecule (chemical)
49
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
50
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
51
What is an inverse agonist?
Decreases the ongoing level of signal
52
What 2 neurotransmitters are involved in peristalsis? What receptor is activated to release them?
Acetylcholine Nitric oxide 5-HT4 receptor
53
What is the action of tubocurarine?
Antagonist Muscle relaxant for surgery Working on ligand-gated sodium channels
54
What is the action of atropine?
Antagonist Inhibits the parasympathetic nervous system - decreases heart rate and saliva Works on G Protein Coupled Receptors
55
What is the action of FP-1039?
Antagonist Cancer therapy (development) Works on tyrosine kinase
56
What is the action of Tamoxifen?
Antagonist Breast cancer treatment Works on nuclear receptors, oestrogen receptor
57
Where are G-protein coupled receptors found?
They are found with the membrane Transmembrane regions
58
What neurotransmitters activate G-protein coupled receptors?
Acetylcholine Serotonin Noradrenaline Hormones
59
What percentage of human drug targets are G-protein coupled receptors?
27%
60
What type of receptor is the 5-HT 4 receptor?
GPCR
61
What are G proteins made up of?
An alpha, beta and gamma subunit
62
Which subunit of a G protein detaches?
Alpha
63
What is 5-HT4 receptor also known as?
Serotonin type 4 receptor (UK) 5 Hydroxy-tryptonine receptor (USA)
64
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
65
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
66
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
67
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
68
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
69
What are the two main plexuses of the enteric nervous system?
Submucosal (Meissner's) | Myenteric (Auerbach's)
70
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
71
When was the enteric nervous system established as a separate functional part of the nervous system?
1970s
72
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
73
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
74
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)
75
What is the primary neurotransmitter in the enteric nervous system?
Acetylcholine
76
What are the different neurotransmitters in the enteric nervous system?
``` Acetylcholine Noradrenaline GABA Nitric oxide Serotonin ```
77
What do the peripheral autonomic nervous pathways contain?
Pre-ganglionic and post-ganglionic neurons
78
What is the small intestine made of?
Duodenum Jejunum Ileum
79
What is the large intestine made of?
Cecum (pouch) Colon (ascending, transverse, descending) Rectum
80
What muscles are involved in peristalsis?
Longitudinal and circular muscles
81
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.
82
What determines the speed at which a drug crosses membranes?
Size of the drug | Lipophilicity of the drug (physiochemical properties)
83
What does transcellular pathway mean?
Through the membrane
84
What does paracellular pathway mean?
Junctions between the cells (water channels, pores, gap junctions)
85
What is the function of goblet cells?
Secreting mucus
86
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
87
What is the main plasma protein that drugs bind to?
Albumin
88
What is the route for the drug to take?
``` In ABSORPTION Blood DISTRIBUTION Tissues ```
89
What drugs can be distributed?
Unbound drugs Unbound to plasma proteins
90
What percentage of the drug usually binds to plasma proteins?
98%
91
What percentage of the drug is free for binding to the target?
2%
92
How does the blood from the stomach, small intestine and large intestine get to the liver?
Hepatic portal vein
93
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
94
What family of enzymes undertakes oxidation in Phase I metabolism?
Cytochrome p450
95
What types of drugs usually undergo Phase I metabolism?
``` Warfarin Anti-depressants Anti-epileptics Statins Codine ```
96
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
97
What molecules are added in Phase II metabolism?
- glutathione - sulphate - glucornide
98
What types of reactions happen in Phase I metabolism?
Hydrolysis | Oxidation
99
What types of reactions happen in Phase I metabolism?
Conjugation
100
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
101
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
102
What are factors that can affect the PKPD ?
Clinical status Nutritional status Co-administration of two or more drugs Gender Weight Patient's age
103
What is the concentration that is required for a drug to work called?
Minimum effective concentration (MEC)
104
What is the concentration that may caused side effects/toxicity called?
Maximum tolerated concentration (MTC)
105
What does a standard plasma concentration/time profile look like?
See graph in powerpoint | Draw out
106
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
107
In principle, how does the body see drugs?
It sees it as toxic and foreign | So it will try and eliminate it asap
108
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
109
What is the therapeutic window?
The range of drug doses (or drug concentration in the plasma) that produces a therapeutic effect
110
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)
111
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
112
What fraction of compounds entering preclinical development?
1/13 compounds
113
How many compounds enter the Drug Discovery stage?
10,000
114
How many compounds enter Pre-clinical trials?
250
115
What type of cells are enterocytes?
Simple columnar epithelial cells
116
How many compounds enter clinical trials?
5
117
How many drugs are FDA review?
1
118
When was the Medicines and Healthcare Regulatory products Agency (MHRA) formed?
2003?
119
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
120
When was the EMA formed?
1993
121
What does the EMA stand for?
European Medicines Agency
122
What does MHRA stand for?
Medicines and Healthcare Regulatory products Agency
123
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)
124
What does FDA stand for?
Food and Drug Administration In the US
125
When was the FDA established?
1927
126
What are the functions of the FDA?
Responsible for regulation and supervision of drug safety Drug assessment, authorisation, post-marketing surveillance
127
Who can report concerns about medicines and devices with the Yellow Card Scheme?
Healthcare professionals and the general public
128
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)
129
What membranes might a drug have to cross if orally absorbed?
Enterocytes in the GI tract Epithelial cells that line the tissues/organs
130
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
131
What is a double blind clinical trial?
Scientists and patients don't know if they are taken the drug or control/ current treatment
132
Why is a double blind clinical trials important
Biased
133
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
134
Where does peristalsis happen?
Oesophagus Stomach Intestines
135
Why was Tegaserod taken off the market?
Withdrawn for increased risk of heart complications Tachycardias and arrhythmias
136
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
137
What is intractable constipation?
Constipation that is prolonged and does not resolve with the usual therapeutic measures
138
What type of receptor is a 5-HT4 receptor?
G Protein Coupled Receptor
140
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
141
What is Tegaserod?
A 5-HT4 agonist used for the management of IBS and constipation
141
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

PBLs FunMed (8 decks)

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