PBL 6

Question 1

Intractable constipation

Answer 1

Constipation that is prolonged and does not resolve with the usual therapeutic measures.

Question 2

Tegaserod

Answer 2

A 5-HT4 agonist used for the management of irritable bowel syndrome and constipation.

Question 3

What type is a 5-HT4 receptor

Answer 3

GPCR

Question 4

what does pharmacodynamics depend on

Answer 4

• depends on receptors and enzymes

Question 5

How does a GPCR works

Answer 5

In resting state GPCR is linked
to an enzyme called a G protein
Ligand binds to the G-protein coupled receptor and this recruits the G trimeric protein which si made outo f the alpha, ebta and gamma, this interacts with GTP and casues it to become activated
The alpha subunit which is now phosphorylated dissociates from the ebta and gamma subunit, this interacts with an effector protein, this could phosphorylate the target protein
Activates the ion channel allowing the transport of ions
Once this has occurs G protein switches off as GTP is hydrolysed to GDP, when the alpha subunit is bound to GDP it is switched off

Question 6

what is distribution

Answer 6

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

Question 7

what is metabolism

Answer 7

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

Question 8

what is excretion

Answer 8

The irreversible transfer of a drug from the systemic circulation

Question 9

what is tegaserod and how does it work

Answer 9

Selective partial agonist that binds with high affinity to 5-HT4 receptors in the colon.
Stimulates the peristaltic reflex and intestinal secretion.
Thus promotes gastric emptying and prevents constipation

Question 10

how does tegaserod stimulate increase peristalsis in the colon

Answer 10

5-HT4 receptor activation by tegaserod stimulates release of neurotransmitters involved in peristalsis which are acetylcholine and nitric oxide
This increases the rate of peristalsis.
Also somehow decreases visceral sensitivity and reduces pain

Question 11

what is the MHRA body

Answer 11

Medicines and Healthcare Products Regulatory Agency (MHRA) is the government body that approves and regulates drugs used in healthcare in the UK.

Question 12

what is the length of a patent in the UK

Answer 12

In the UK, the length of a patent is 20 years and can be extended for an additional 5 years.

Question 13

Describe pre clinical testing

Answer 13

Uses 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.

Question 14

describe phase 0

Answer 14

First time the drug is given to humans (a small group of about 10 healthy individuals).
First time pharmacodynamics and pharmacokinetics can be observed in vivo.
Checks for any harmful, unforeseeable side effects of the trialed drug.

The Dosage is much smaller than what would be sold on the market as a therapeutic amount as this is the first time pharmacodynamics and pharmacokinetics can be observed in vivo

Question 15

Describe phase 1

Answer 15

Still with healthy volunteers.
Size of the cohort is expanded.
A dose escalation study is implemented to determine the most appropriate dosage required to produce the desired effect.

Question 16

Describe phase 2

Answer 16

First time that actual patients with the condition the new drug has been developed to treat are involved.
Few hundred participants are either given a placebo or the actual drug that is being tested.
Assesses the effectiveness of the new drug by subtracting the placebo’s efficacy from that of the trialled drug.

If there is no significant difference between the efficacy of the placebo and the new drug, the trial may be cancelled at at this stage.

Question 17

Describe phase 3

Answer 17

Similar to phase 2, but importantly, there may be several thousands of patients involved.
Enables reliability of the data obtained to be maximised.
Benefits of the new drug are weighed against side effects.

Question 18

Describe phase 4

Answer 18

Continuous testing and review of the effects of the drug as it is being marketed and sold to the public.
If this does occur, patients can feedback about the effects of the drug to appropriate bodies through the yellow card scheme put in place by the MHRA.

Question 19

Besides binding to its target, what other properties must an oral drug have in order to exert its maximum effect in the body? Give 4 examples.

Answer 19

Dissolve
Survive a range of pHs (1.5-8.0)
Survive intestinal bacteria
Survive liver metabolism
Avoid excretion by kidneys
Avoid partition to non-target organ

Question 20

What is the main route for oral drug absorption?

Answer 20

Passive diffusion via the transcellular pathway (1). This occurs through enterocytes (which are simple columnar epithelial cells (1)).

Question 21

describe different drug targets antagonists

Answer 21

Antagonsit that are important
Tubucuraine – muscle relaxant for surgery
Atropine – inhibits parasympathetic nervous system decreasing HR/saliva
Tamoxifen – binds to the osetrogen receptor and therefore prevent high levels of osterogen to occur and inhibit growth of the breast cells, used as breast cancer treatment

Question 22

describe the structure and function of GI tract

Answer 22

Muscosal and muscle layers - controlled by the action of intrinsic nerves (the enteric nervous system) and extrinsic nerves of (mainly) the autonomic nervous system control motility, secretion, absorption and peristalsis. - have absorptive cells in them
Circular and longitudinal smooth muscle responsible by peristalsis

Question 23

What is the route of oral drug absorption

Answer 23

Drug must cross membranes (e.g. epithelial/endothelial cells).

Most drugs cross membranes via passive diffusion (high to low concentration). The speed at which the drug is move is determined by the size and the lipophilicity of the drug

This will be determined by size and lipophilicity of drug –
(physicochemical properties).

Question 24

factors affecting absorption

Answer 24

Acid stability
Tablet - pass through the stomach (pH ~ 1) before it gets into the systemic circulation - drug needs to be stable to these acidic conditions at body temperature.
The pH of the small intestine is ~ 7 - majority of absorption often takes place here, due to the comparatively large surface area.

Solubility
The drug requires sufficient aqueous solubility for dissolution, as only dissolved
compound can be absorbed.

Permeability
Poor permeability, gut wall metabolism and/or efflux can all lead to poor
absorption across the intestinal wall.

Lipophilicity
Drugs which are absorbed passively through the gut wall also need to be
sufficiently lipophilic to cross cell membranes but polar enough to be sufficiently
water soluble.

Question 25

describe the bioavailability of tegasegord

Answer 25

Tegarserod – only 2% avalaible to enter as 98% boudn to alumbimin

Question 26

Define the therapeutic window

Answer 26

The therapeutic window is the range of drug doses (or drug concentration in the plasma) that produces a therapeutic effect.

Question 27

What does the MHRA do

Answer 27

Side effects (adverse drug reactions or ADRs)
Medical device 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)

Question 28

what does the EMA do

Answer 28

• coordinates the evaluation and supervision of the new medical products, grants option on licensing and oversees pharmocovilgilance

Question 29

what does FDA do

Answer 29

• responsibly for regulation and supervision of drug safety; drug assessment and authorisation, post-marketing surveillance

Question 30

why was teagserod withdrawn

Answer 30

Withdrawn for increased risk of heart complications. – similar receptors on the heart, tachycardia and arthymia

A 5HT4 receptor agonist called prucalopride (Shire Pharmaceuticals) approved for use in Europe for constipation in females.

The EMA approved this compound after extensive demonstration of cardiac safety.