Cholinergic & NorAdrenergic Transmission

Question 1

ANS

Answer 1

• The ANS governs the function of organ systems which are not controlled by conscious inputs from the brain cortex- Subdivided into sympathetic and parasympathetic divisions
• Under normal conditions, most organs receive a balanced dual innervation
• Responsible for homeostasis- Maintains constant internal environment (visceral organs)
• Hypothalamus - Controls: Respiration, Cardiac regulation, Vasomotor activity, digestive reflex actions

Question 2

Connecting the ANS to the PNS

Answer 2

• Sympathetic preganglionic axons enter a sympathetic chain ganglion via white ramus communications
• Rami communicans= the communicating nerve branch between sympathetic ganglions and spinal nerve
• Postganglionic axons exit sympathetic chain through gray rami communicans & enter the spinal nerve

Question 3

Sympathetic Division- (Fight or Flight)

Answer 3

• Thoracolumbar outflow- All nerves come from thoracic or lumbar regions
• Sympathetic ganglions are quite far away from target organs
• Short pre-ganglionic fibres- NT= acetylcholine- acts on nicotinic receptor
• Long post-ganglionic fibres- NT= noradrenaline (adrenergic)

Question 4

Parasympathetic Division- (Rest and Digest)

Answer 4

• Craniosacral outflow- All nerves come from the cranial or sacral regions
• Ganglions are often very close to target organ
• Long pre-ganglionic fibres- NT= acetylcholine- acts on nicotinic receptor
• Short post-ganglionic fibres- NT= acetylcholine- acts on muscarinic receptor

-The sympathetic and parasympathetic can have opposing effects on the same target cell/organ because they employ different neurotransmitters that bind distinct receptors

Question 5

Basic Cellular Organisation of CNS

Answer 5

• Normally there’s a 2 neurone chain
• between the spinal cord to the
• viscera
• Exception to this rule: Adrenal Gland
• The adrenal medulla receives direct synaptic input from preganglionic neurons–> activates chromaffin cells of the adrenal medulla–> adrenaline release –> circulation
• Chromaffin cells act as a specialised postganglionic cell

Question 6

Acetylcholine

Answer 6

Synthesis- Choline + Acetyl-CoA –> choline acetyl transferase –>Acetylcholine

Breakdown- Acetylcholine–> acetylcholinesterase–> Choline + Acetate

Rapid hydrolysis of Ach (within 1-2ms) ensures a brief duration of action

Question 7

Cholinergic Receptors

Answer 7

• Muscarinic (GPCR)- The response is excitatory or inhibitory
• M1-M5 at glands, CVS, and viscera
• Selectively stimulated by muscarine, Blocked by antimuscarinics e.g. atropine
• Nicotinic (ligand-gated ion channel)- The response is short & excitatory
• N2 (or NN) at autonomic ganglia (N1/ Nm at NMJ i.e. not ANS)
• Selectively stimulated by nicotine, N2 blocked by ganglion blockers e.g. hexamethonium

Question 8

Muscarinic Receptor Subtypes

Answer 8

• M1 receptors (G-protein (Gq) coupled to phospholipase C)
• Stimulates gastric acid secretion
• M2 receptors (G-protein (Gi) coupled to potassium channels)
• mediate the negative chronotropic effects of parasympathetic stimulation, Slows heart rate
• M3 receptors (G-protein (Gq) coupled to phospholipase C)
• mediate lacrimal and salivary gland secretion, and may also be involved in gut smooth muscle contraction.
• M4 and M5 subtypes are thought to be present mainly in the CNS, although M4 receptors (Gi, coupled to potassium channels) may also mediate adrenaline secretion from the adrenal medulla

Question 9

Drugs Acting on Parasympathetic NS

“Parasympathomimetics”

Answer 9

• stimulates the parasympathetic NS*
• Muscarinic receptor agonists (v.few of clinical use):
• Muscarine (not therapeutic)
• Bethanechol (M3) treat urinary retention
• Pilocarpine (M3) induce salivation, treat glaucoma
• Anticholinesterases (common to the somatic NS) (potentiate action of ACh by inhibiting its hydrolysis)
• E.g. physostigmine neostigmine pyridostigmine edrophonium

Question 10

Drugs Acting on the Parasympathetic NS

“Parasympatholytics”

Answer 10

• block the parasympathetic NS*
• Muscarinic receptor antagonists
• Atropine (non-selective M1-M3) used to ↑ heart rate, dilate pupils
• Ipratropium used in COPD & asthma
• Pirenzepine used in peptic ulcers

Question 11

Noradrenaline Synthesis

Answer 11

• Tyrosine –> Tyrosine hydroxylase–> L-DOPA–> Dopa decarboxylase–> dopamine–> dopamine β- hydroxylase –>noradrenaline
• Noradrenaline –>N-methyl transferase (restricted to adrenal medulla) –>adrenaline

Question 12

Noradrenaline Receptors

Answer 12

Two major classes of receptors (GPCRs) for noradrenaline:

1. Alpha-adrenergic receptors:

GPCR (Gq)- phosphatidylinositol signal pathway

• α1- vascular smooth muscle, iris, gut, uterus, salivary gl., bladder (Higher affinity for noradrenaline)
• α2- presynaptic, vascular smooth muscle, gut, brain

2. Beta-adrenergic receptors

GPCR (Gs)- cAMP signal pathway

• β1- heart
• β2- uterus, airway &vascular smooth muscle (higher affinity for adrenaline)
• β3- adipose tissue
• Most agonists and antagonists at cathecolamine receptors interact with more than one receptor type

Question 13

Noradrenaline Breakdown

Answer 13

• Norepinephrine can be recycled in the presynaptic neuron by an uptake mechanism & can be catabolized –> inactive compound through the sequential action of cathecolamine-Omethyltransferase and monoamine oxydase (MAO).

Question 14

Sympathomimetic Drugs

Answer 14

• Used in conditions where it is appropriate to ↑ BP by stimulating the heart & inducing vasoconstriction.
• Longterm use of sympathomimetics= deleterious, they are used for short-term treatment of refractory heart failure, cardiogenic shock, and hypotension caused by hemorrhage or sepsis.
• Isoprenaline is used to ↑HR in cases of bradycardia (slow heartbeat). b1,b2 adrenoreceptor agonist
• Salbutamol is used to relax the bronchi in cases of asthma & is the drug used in some ‘inhalers’. It is marketed under the name Ventolin. b2 adrenoreceptor agonist
• Also nasal decongestants and appetite suppressants- Hypertensives

Question 15

Sympatholytic Drugs

Answer 15

Block the sympathetic adrenergic system at 3 levels:

1. Alpha and beta receptor antagonists: block the influence of noradrenaline at the effector organ
2. Ganglionic blockers: block impulse transmission at the sympathetic ganglia
3. Drugs that block sympathetic activity within the brain

• Tend to decrease heart rate and blood pressure- Antihypertensives
• Inhibitors of NAd synthesis, release, reuptake e.g. Methyldopa, Reserpine, Guanethidine
• a1/a2 receptor antagonists (“alpha blockers”) e.g. Phentolamine, Phenoxybenzamine Prazosin (α1),Yohimbine (α2)- Treats anxiety
• b1,2 receptor antagonists (“beta blockers”) e.g. Propranolol (b1,b2), Metoprolol (b1), Atenolol (b1)-Treats anxiety