Chemical Mediators 3

Question 1

What is the endocrine system?

Answer 1

It’s a network of glands and hormones which is important in regulating metabolism, growth and reproduction
Relies upon rapid nerve impulses and it uses chemicals for long-term regulation

Question 2

Parts of the endocrine system

Answer 2

Pituitary Gland: Often termed the ‘master gland’; controls other endocrine glands.
Thyroid Gland: Regulates metabolism, energy generation, and growth.
Parathyroid Glands: Crucial for calcium balance in the body.
Adrenal Glands: Produce hormones like adrenaline and cortisol, essential for stress response.
Pancreas: Key in glucose regulation; produces insulin and glucagon.
Gonads (Ovaries/Testes): Responsible for producing sex hormones and gametes.

Question 3

What is serotonin (5-hydroxytryptamine) ?

Answer 3

-neurotransmitter in the brain and periphery
-acts as a local hormone in the peripheral vascular system
-shown to be originated from platelets
-formed from dietary tryptophan; chocolate, oats etc

Question 4

Where can 5-HT be found in the body?

Answer 4

-in the gut, 90% of the total amount is in the intestine, enterchhromaffin cells and some in enteric neurones of the intestine
-in the blood; platelets
-in the CNS

Question 5

More about 5-HT;
Where does endogenous 5-HT arise from?

Answer 5

-most 5-HT is present in the diet however most of this is metabolised before entering the bloodstream
-arises from a biosyntehtic pathway similar to that which generates noradrenaline, except that precursor amino acid; tryptophan instead of tyrosine

Question 6

Distribution and biosynthesis of tryptophan?

Answer 6

• Tryptophan is converted to 5- hydroxytryptophan (in chromaffin cells and neurones, but not in platelets) by the action of tryptophan hydroxylase.
• The 5-hydroxytryptophan is then decarboxylated to 5-HT by a ubiquitous amino acid decarboxylase that also participates in the synthesis of catecholamines and histamine
- platelets posses a high affinity 5-HT uptake mechanism and platelets become loaded with 5-HT as they pass through the intestinal circulation; where the local conc is high

Question 7

Distribution and biosynthesis of tryptophan; continued

Answer 7

-mechanisms of synthesis, storage, release and reuptake of 5-HT are very similar to noradrenaline
-many drugs affect both processes but selective serotonin reuptake inhibitors= been developed and are important therapeutically as antidepressants
-5-HT is stored in neurones and chromaffin cells as a cotransmitter together with various peptide hormones; e.g. somatostatin

Question 8

Describe the process of the degradation of 5-HT:

Answer 8

-occurs mainly through oxidative deamination, catalysed by monoamine oxidase, followed by oxidation to 5-hydroxyindoleacetic acid pathway (same as noradrenaline catabolism)
-excreted in urine and serves as an indicator of 5-HT production in the body
^ used for stuff like; diagnosis of carcinoid syndrome

Question 9

Biosynthesis and metabolism of 5-HT

Answer 9

Slide 11

Question 10

What are the actions + functions of 5-HT?

Answer 10

-increased gastrointestinal motility (direct excitation of
smooth muscle and indirect action via enteric neurones)
– contraction of other smooth muscle (bronchi, uterus)
– mixture of vascular constriction (direct and via
sympathetic innervation) and dilatation (endothelium-
dependent)
– platelet aggregation
– stimulation of peripheral nociceptive nerve endings
– excitation/inhibition of central nervous system
neurones

Question 11

What does postulated physiological pathophysiological roles include?

Answer 11

in periphery: peristalsis, vomiting, platelet aggregation and haemostasis, inflammatory mediator, sensitisation of nociceptors and microvascular control
in CNS: many postulated functions, including control of appetite, sleep, mood, hallucinations, stereotyped behaviour, pain perception and vomiting.

Question 12

Clinical conditions associated with disturbed 5-hydroxytryptamine function:

Answer 12

Migraines, carcinoid syndrome, mood disorders and anxiety

Question 13

Pharmacological effects:

Answer 13

Actions of 5HT is complex (reflects a profusion of 5HT receptor subtypes) and a lot
14 types / subtypes of different receptors

Question 14

Main sites of action:

Answer 14

Gut
Blood vessels
Platelets
Smooth muscle
Nerve endings
CNS

Question 15

5-Hydroxytryptamine receptors

Answer 15

Pharmacology lecture 9 chemical mediators 3
Slide 17-19

Question 16

Non-adrenergic Non-cholinergic (NANC) transmitters and co-transmitters:

Answer 16

Issue- explanation of responses obtained following stimulation of ANS in the presence of adrenergic and cholinergic antagonists/blockers

Explanation is that many chemical messengers unrelated to Ach or Ad co-exist in and are released concomitantly by single neurones.

This lead to the development of the concept of NANC transmission.

Question 17

NANC transmitters classes:

Answer 17

Purines
Neuropeptides
Nitric Oxide

Question 18

Purine class:

Answer 18

For example:
Adenosine (nucleosides), not stored in the vesicles, it has a cytoplasmic location.
ATP, ADP (nucleotides)
Produce a wide range of pharmacological effects that are unrelated to their role in energy metabolism.

Purines participate in many physiological control mechanisms including
Regulation of coronary flow
myocardial function,
platelet aggregation and immune responses
neurotransmission in both the central and peripheral nervous system

Question 19

Purine class roles:

Answer 19

Purines have important roles in chemical signalling in the periphery and CNS, both as primary neurotransmitters and as co-transmitters.
ATP is stored and released along with NA and Ach from nerve ending innervating smooth muscles.
It accounts for many of the actions produced by stimulation of autonomic nerves that are not caused by acetylcholine or noradrenaline.

Question 20

The effects of ATP after nerve stimulation:

Answer 20

Relaxation of intestinal smooth muscle evoked by sympathetic stimulation
Contraction of the bladder produced by parasympathetic nerves.

Question 21

Purines as mediators:

Answer 21

ATP (and in platelets, ADP) is stored in vesicles and released by exocytosis. It is also present in the cytosol of all cells, from which large quantities may be released by cellular damage. Adenosine is present in the cytosol of all cells, and is taken up and released via a specific membrane transporter. Released ATP and ADP are rapidly converted to adenosine by the action of tissue nucleotidases.

Question 22

Purine receptors:

Answer 22

There are two main types :
P1 receptors (subtypes A1, A2 and A3). These are GPCRs that respond to adenosine and are present in many different tissues. They are linked to stimulation or inhibition of adenylate cyclase.
P2 receptors (subtypes P2X and P2Y, each with several further subdivisions). These respond to ATP and/or ADP. P2X receptors are multimeric ionotropic receptors, whereas P2Y receptors are GPCRs coupled to adenylate cyclase or phosphoinositide metabolism.

Question 23

Pharmacological aspects of uses of adenosine:

Answer 23

Because of its inhibitory effect on cardiac conduction, adenosine may be used as an intravenous bolus injection to terminate supraventricular tachycardia.

It is safer than alternative drugs such as β-adrenoceptor antagonists or verapamil, because of its short duration of action.
Otherwise, adenosine is not used therapeutically, although longer-lasting A1 receptor agonists might prove useful in various conditions (e.g. hypertension, ischaemic heart disease and stroke).
Selective adenosine receptor antagonists could also have advantages over theophylline in the treatment of asthma

Question 24

Drugs acting on purine receptors:

Answer 24

Methylxanthines, especially analogues of theophylline are A1/A2 receptor antagonists; however, they also increase cAMP by inhibiting phosphodiesterase, which contributes to their pharmacological actions independently of adenosine receptor antagonism.
CNS stimulation by methylxanthines such as caffeine is partly a result of block of inhibitory A1/A2 receptors.
Certain derivatives of theophylline are claimed to show greater selectivity for adenosine receptors over phosphodiesterase.
P2 receptors are blocked by suramin and the experimental compound PPADS.