pharmacology and physiology of receptors

Question 1

what do somatic efferent nerves do ?

Answer 1

neurons from the CNS release the neurotransmitter acetylcholine that acts on nicotinic receptors on skeletal muscle - this is under voluntary control.

Question 2

whats the autonomic nervous system?

Answer 2

the autonomic nervous system controls involuntary bodily functions. it has subconscious control of organs and homeostasis controlling all outputs from the CNS apart from somatic motor innervation to skeletal muscle.

Question 3

the autonomic nervous system can be subdivided into the sympathetic and parasympathetic nervous system. what nerves are present in the sympathetic nervous system?

Answer 3

• short preganglionic nerves release ACH that acts on nicotinic receptors of the ganglion, the post ganglionic nerve then releases noradrenaline which has affects on the body like dilation of blood vessels.
• short preganglionic nerves release ACh that acts on nicotinic receptors of the ganglion so the long post ganglionic nerve releases acetylcholine - this acts on muscarinic receptors like in the sweat glands.
• a single nerve releases acetylcholine that acts on nicotinic receptors of the adrenal medulla trigerring the release of adrenaline.

Question 4

what does the parasympathetic nervous system do?

Answer 4

a long preganglionic nerve releases acetylcholine that acts on nicotinic receptors of the ganglion so the post ganglionic nerve releases acetylcholine that acts on muscarinic receptors in the body like the salivary glands.

Question 5

what are some of the functions of the ANS?

Answer 5

• contraction and relaxation of smooth muscle in blood vessels and organs
• regulation of glandular secretion
• control of heart rate
• metabolism

Question 6

a third branch of the ans is the enteric branch, what is this?

Answer 6

cells in the wall of the GI tract have a myenteric plexus and submucosal plexus - this is a local circuit of nerves around smooth muscle allowing contractions of the GI tract without signalling from the brain. it recieves sympathetic and parasympathetic input, innervating blood vessels, smooth muscle and glands and includes sensory neurons and interneurons.

Question 7

what neurotransmitters does the enteric branch of the ANS make use of?

Answer 7

acetylcholine, noradrenaline and non-adrenergic non-cholinergic (NANC)

Question 8

what does the enteric branch enable us to do pharmacologically?

Answer 8

we can use neurotransmitters/receptors as drug targets to act upon the GI tract.

Question 9

what are the nerves of the sympathetic nervous system? (where do they branch from and what organ/gland do they innervate?)

Answer 9

• nerves innervate the salivary glands branching off from the cervical and thoracic spine
• nerves from the thoracic spine act on the GI tract
• nerves from the thoracic and lumbar spine act on the bladder

Question 10

what are some of the nerves of the parasympathetic division?

Answer 10

• nerves branching off cranial/medullary affect the salivary glands and upper GI tract (up to the duodenum)
• sacral nerves act on the lower GI tract (past the duodenum) and the bladder

Question 11

sometimes sympathetic and parasympathetic stimulation have opposing actions, give an example of this.

Answer 11

the sympathetic nervous system would increase the heart rate and deactivate smooth muscle of the gut where as the parasympathetic nervous system will slow down hear rate and activate the smooth muscle of the gut and bladder.

Question 12

in what ways would activation of the sympathetic and parasympathetic nervous system have the same effects?

Answer 12

salivation

Question 13

what organs only have innervation of the sympathetic ns?

Answer 13

sweat glands and blood vessels

Question 14

what organs only have parasympathetic innervation?

Answer 14

ciliary muscle of the eye

Question 15

describe the physiology of the preganglionic neuron.

Answer 15

the cell body of the preganglionic neuron is located in the CNS, it has a small diameter and is myelinated, it has synapses at the autonomic ganglia, preganglionic fibres release acetylcholine that acts on nicotinic receptors on the post ganglionic neuron.

Question 16

describe the physiology of the post ganglionic neuron.

Answer 16

the cell body of the post ganglionic neuron is in the autonomic ganglion, it has a small diameter and is unmyelinated - the terminal synapse is near the target organ.

Question 17

how is the adrenal medulla an exception?

Answer 17

the adrenal medulla is not a two neuron system - consider the adrenal medulla as a specialised ganglion and the chromaffin cells are specialised post synaptic neurons.

Question 18

cholinergic receptors mediate the effects of acetyl choline. what are the two types of cholinergic receptors?

Answer 18

• nicotinic - ligand gated ion channels with two main types;neuronal and neuromuscular
• muscarinic - these are g protein coupled receptors - when activated by acetylcholine the g proteins mediate down stream effects. there are 5 types of muscarinic receptor.

Question 19

outline the functions of m1 m3 and m5 muscarinic receptors.

Answer 19

m1 m3 and m5 all have the same signalling pathway. when activated g protein binds to the C teminal of the receptor causing increased IP3 and stimulating an increase in Ca2+ concentration hence causng muscle contraction.

Question 20

where can m1 receptors be found?

Answer 20

in gastric and salivary glands

Question 21

where can m3 receptors be found?

Answer 21

in salivary and gastric exocrine glands, smooth muscle of the GI tract, eye, airways, bladder and endothelium of blood vessels

Question 22

where can m5 receptors be found?

Answer 22

in salivary glands, the iris and ciliary muscle

Question 23

how does the m2 receptor work?

Answer 23

activation of the G protein coupled rceptor causes reduced cAMP causing a reduction in calcium conductance and an increase in potassium conductance - this results in neural and cardiac inhibition and central effects. M4 also causes reduced cAMP and affects the CNS.

Question 24

what would muscarine poisoning cause?

Answer 24

muscarine poisoning leads to excessive parasympathetic responses like salivation, lacrimation, urination, diarrhoes, gastric upset and vomiting.

Question 25

what drugs directly affect muscarinic receptors?

Answer 25

• muscarinic agonists (parasympathomimetic) will mimic the affects of acetylcholine, activating the muscarinic receptors.
• muscarinic antagonists (parasympatholytic) will block the affects of acetylcholine inhibiting the activation of muscarinic receptors

Question 26

what drugs indirectly affect muscarinic receptors?

Answer 26

inhibitors of acetylcholine breakdown (parasympathomimetic) hence increasing the activation of muscarinic receptors.

Question 27

what are sme examples of muscarinic agonists?

Answer 27

acetylcholine, methacholine, carbachol, bethanechol and pilocarpine - they are all agonists that act on muscarinic receptors.
acetyl choline, methacholine and carbachol also have some effect on nicotinic receptors.
acetylcholine and methacholine also work on acetylcholinesterase hydrolysis.

Question 28

what predicts the M selectivity?

Answer 28

the addition of methyl groups affects the selectivity for particular muscarinic receptors.

Question 29

bethanechol is a stable hybrid of carbachol and methacholine, its selective for muscarinic receptors and stable to hydrolysis by AChE. what is it used for?

Answer 29

bethanecol is occasionally used to stimulate bladder and GI function.

Question 30

pilocarpine is a partial agonist - what is it selective for?

Answer 30

pilocarpine is relatively selective for secreation from sweat, salivary, lacrimal and bronchial glands and contracting smooth muscle of the iris. it crosses the BBB so it has central effects.

Question 31

what can pilocarpine be taken form?

Answer 31

it may be used for dry eyes or dry mouth due to its effects on the lacrimal and salivary glands.

Question 32

what do muscarinic antagonists do?

Answer 32

muscarinic antagonists, also known as parasympatholytics cause inhibition of secretions and GI motility, smooth muscle relaxation, bronchodilation, CNS excitation and tachycardia.

Question 33

what is atropine?

Answer 33

atropine is a non selective competitive muscarinic antagonist hence it binds to all muscarinic receptors. it is readily absorbed and penetrates the BBB stimulating the CNS and causing hallucinations.

Question 34

what are the cliniccal uses of atropine?

Answer 34

atropine dries secretions, treats anticholinesterase poisoning, treats bradycardia and treats GI hypermotility.

Question 35

what are darifenacin and oxybutynin and what are they used for?

Answer 35

darifenacin and oxybutynin are both M3 selective antagonists that inhibit involuntary bladder contraction - they can therefore be used to treat urinary incontinence.

Question 36

what are the drugs hyoscine and scopolamine and what are they used for?

Answer 36

hyoscine and scopolamine are non selective competitive antagonists that cause GI relaxation and are also anti secretory. it is a CNS depressant so has a sedatory effectand blocks transmission from vestibular apparatus to the vomiting centre.
clinically, hyoscine and scopolamine is used for bowel pain in IBS, motion sickness, respiratory secretions in palliative care and adjunct to anaesthesia.

Question 37

what is pirenzapine and how does it work?

Answer 37

pirenzapine is a muscarinic M1 selective antagonist - it inhibits vagus induced histamine release - the pirenzapine binds to the m1 receptor so when the vagus nerve releases acetlycholine it will not trigger the G cell to release gastrin which would usually cause the enterochromaffin like cells to release histamine. the histamine usually produced works on H2 receptors of the parietal cells causing release of H+ . pirenzapine was therefore used to treat gastric ulcers by lowering the acidity of the stomach. Hwoever M3 receptors on the parietal cell can still be activated by acetylcholine triggering H+ release via this pathway.

pirenzapine has no direct effects on smooth muscle and little CNS effect as it does not cross the BBB.

Question 38

histamine is a tissue amine - where can it be found?

Answer 38

histmine is present in tissue mast cells throughout the body and also found in enterochromaffin like cells with neuroendocrine function in the gastric mucosa.
histamine is also in the CNS in the hypothalamic neurons with axons throughout the CNS.

Question 39

what are some exogenous forms of histamine?

Answer 39

histamine is also present in some foods like fish pickles and cheese, although this is not well absorbed after ingestion.
histamine is also released by nettles hence causing a stinging sensation by affecting sensory nerves in the skin.

Question 40

what is histamine derived from?

Answer 40

histamine, also known as histidine decarboxylase is derved from histidine.

Question 41

after release, histamine has 2 major metabolic pathways - what are these?

Answer 41

• elimination of H close to the R by N-methyl transferase to produce N-methylhistamine
• elimination of H excess by diamine oxidase to produce imidazolyl acetoaldehyde.

Question 42

how is histamine stored within mast cells?

Answer 42

histamine is stored in mast cell granules bound to heparin (this is acidic and therfore oppositely charged) in order to stop it from leaking out until the release is triggered.

Question 43

what happens when the mast cell is activated?

Answer 43

when the mast cell is activated, the granules bind to the cell membrane and release histamine from the cell.

Question 44

what affect does histamine have when released in the GI tract?

Answer 44

Histamine in the GI tract will cause increased peristalsis (motility)

Question 45

what are some of the stimuli that activate mast cells to release histamine?

Answer 45

• mechanical injury to skin - hence why it swells and turns red
• chemicals like insect bites
• drug reactions - like opiods
• allergy - a type 1 immediate hypersensitivity via IgE on mast cells. e.g. allergic rhinitis/hayfever or urticuria.

Question 46

there are 4 types of histamine receptors all of which are G protein coupled receptors consisting of 7 transmembrane receptors with a G-protein coupled on. Whats does activation of H1 cause?

Answer 46

when the H1 histamine receptor is activated it stimulates phospholipase C triggering an increase in Ca2+ - this drives smooth muscle contraction and some secretion. Protein kinase C is also released.

Question 47

what happens when H2 is activated?

Answer 47

when the H2 receptor is activated it stimulates adenylyl cyclase activating protein kinase A which will have biological affects.

Question 48

what happens when H3 is activated?

Answer 48

Activation of the H3 receptor will inhibit the release of adenylyl cyclase which will lead to a fall in protein kinase A activity.

Question 49

what happens when the H4 receptor is activated?

Answer 49

activation of the H4 receptor will inhibit adenylyl cyclase causing a reduction in protein kinase A activity. It will also activate phospholipase C increasing the activity of protein kinase C and the amount of Ca2+ by beta and gamma subunits.

Question 50

how is histamine involved in inflammation?

Answer 50

histamine release helps promote beneficial inflammation by allowing blood vessels to be more leaky so plasma can leak into the tissue and help.

Question 51

how does histamine promote the removal of parasites from the gut?

Answer 51

mast cell derived histamine will cause gut contraction, fluid permeability, diarrhoe and chemoattraction of immune cells hence helping remove parasites from the gut.

Question 52

what are two other phsyiological roles of histamine?

other than removal of parasites and beneficial inflammation

Answer 52

• gastric acid secretion
• in the brain histamine stimulates wakefulness centres to keep us alert - this can lead to negative side effects for antihistamines, many do cause drowsiness.

Question 53

histamine activates H1 receptors to cause inflammation - what are the responses that lead to inflammation?

Answer 53

• activation of the H1 receptor causes vasodilation of arterioles via nitric oxide release from the endothelium - this means there is increased blood flow to the affected site, also causing rubor/redness
• vascular permeability will increase via endothelial contraction making the cells more leaky leading to oedema.
• histamine will activate sensory nerves causing pain and itch - itching will cause more mechanical damage to the skin stimulating more histamine release in a vicious cycle.

Question 54

how are h2 receptors involved in inflammation?

Answer 54

activation of h2 receptors casues vasodilation of vascular smooth muscle, although this has little importance in inflammation.

Question 55

what is the cutaneous response to histamine?

Answer 55

• flush - local vasodilation via H1 receptors on the blood vessel will cause reddening
• wheal - endothelial cell contraction via H1 receptors will lead to oedema formation
• flare - sensory nerve activation by H1 receptors will release dilator neuropeptides that will spread from the site of injury

Question 56

explain the pathway of events leading to inflammation when a mast cell is triggered.

Answer 56

histamine released by the mast cell acts on h1 receptors of blood vessels causing vasodilation and oedema. the histamine also acts on sensory nerve C fibre causing pain and itch - the sensory nerve also releases the neuropeptides neurokinin A and cGRP (calcitonin gene related peptide) which further act on blood vessels to increase vasodilation and oedema.
neurokini A from the sensory nerve also acts on the mast cell so that more histamine is released.

Question 57

outline the h1 receptor antagonists and how they work

Answer 57

chlophenamine is a h1 receptor antagonist blocking h1 receptors so histamine cant bind. however it can cross the BBB so can also cause drowsiness.
newer second generation antihistamines like loratidine and astemizole have lower lipophilicity so they dont cross the BBB and are therefore non drowsy.

Question 58

what are h1 antagonists good for?

Answer 58

urticaria and nasal congestion

Question 59

h4 antagonists are undergoing clinical trials but there are none on the market, what are they for?

Answer 59

the h4 histamine receptor is highly expressed on white blood cells causing leukocyte chemotaxis and activation - it also acts on sensory nerves to trigger pain and itch pathways. h4 antagonists could be used as antiinglammatory agents.

Question 60

how is histamine involved in wakefulness? could this be utilised?

Answer 60

histaminergic nerves in the hypothalamus access the cerbral cortex with central histamine release causing wakefulness - it is H1 receptor mediated hence why H1 antagonists may cause drowsiness if theyre CNS penetrating.
we could increase central histamine release to increase wakefulness to treat narcilepsy, however this would cause systemic effects.

Question 61

histamine release in the CNS is H1 mediated - how is the H3 receptor involved?

Answer 61

there is a presynaptic H3 receptor on the histaminergic neuron which regulates the synthesis and release of histamine and other neurotransmitters in the CNS. when the histaminergic neuron releases histamine it not only acts on H1 receptors causing alertness, but also acts on H3 receptors to negatively feedback so the histamine release is regulated.

Question 62

what would happen if we block H3 receptors?

Answer 62

H3 receptors inhibit the release of histamine from central nerves via H3 autoreceptors. we can therfore block central H3 receptors to enhance histamine release.

Question 63

what does it mean that H3 receptors have high basal activity?

Answer 63

h3 receptors will be active without a ligand

Question 64

what does ciproxifan do?

Answer 64

ciproxifan is an inverse agonist - it will lower H3 receptor signalling evem in the absence of an agonist. this will therefore increase wakefulnessand could be used as a potentil treatment for narcilepsy, dementia or adhd - although its not licensed atm.

Question 65

how is histamine involved in the secretion of gastric acid?

Answer 65

enterochromaffin like cells in the GI tract will release histamine under hormonal control. the histamine then acts on h2 receptors of parietal cells stimulating the parietal cell to release H+ to help aid digestion. however, increased stomach acid can cause ulcers.

Question 66

outline the pathway leading to gastric acid secretion.

Answer 66

the vagus nerve releases acetylcholine that acts on M1 muscarinic receptors on G cells, the G cells then release gastrin which stimulates the enterochromaffin like cell to release histamine which binds to H2 receptors of parietal cells so that H+ is released.

Question 67

how can we reduce stomach acid levels?

Answer 67

we can give h2 receptor antagonists, howevere the vagus nerve still rleases ACh that acts on M3 muscarinic receptors of the parietal cell so H+ is still released.

Question 68

what are some of the H2 receptor antagonists used to lower gastric acid secretions?

Answer 68

cimetidine is a selective H2 receptor antagonist that blocks gastric acid secretion via H2 receptors on parietal cells. however cimetidine has many drug interactions as it is a CYP inhibitor, reducing phase 1 metabolism, reduces renal clearance, decreases hepatic blood flow reducing liver excretion and its effect on gastric pH increases the absorption of acid labile drugs.
ranitidine and famotidine are alternatives with fewr side effects.