Topic 1: Autonomic Nervous System

what processes does the ANS regulate:

• SM contraction/relaxation

• all exocrine + some endocrine secretions

• heart rate

• intermediary metabolism

what is the relationship between sympathetic and parasympathetic nervous systems and which predominates in what states?

• opposing actions in some physiological systems

• sympathetic NS activity increases in stress (flight/fight)

• parasympathetic NS activity predoms during satiation and repose

What neurons are involved in ANS structure and what arrangment is it?

• 2 neurons arranged in series:

  1. preganglionic

  2. postganglionic

What is the anatomy of sympathetic and presympathetic neurons

sympathetic = SHORT pregang + LONG postgang neurons
parasympathetic = LONG PREgang + SHORT POSTgang

which neuronal cell bodies are located in the lateral horn of grey matter of thoracic and lumbar segments of the spinal cord

sympathetic preganglionic neurons

what is the arrangment of sympathetic neurons in the body

1. preganglionic neuronal cell bodies are located in lateral horn of grey matter of Thoracic and Lumbar segments of spinal cord

2. these connect to the prevertebral chain of sympathetic ganglia (contain cell bodies of postganglionic neurons)

3. postganglionic fibres reach peripheral destinations via branches of spinal nerves

4. fibres for pelvic and abdominal sites have cell bodies in prevertebral ganglia in abdominal cavity

What is the exception to the two neuron arrangment in the sympathetic NS

• Adrenal medulla: innervation of adrenal medulla which releases catecholamines when stimulated and considered to be modified postgang sympathetic neuron

• Adrenal Medulla: Modified postganglionic sympathetic neuron that releases catecholamines (epinephrine and norepinephrine) into the bloodstream.

what two outflows do parasympathetic preganglion neurons exit out of

1. cranial outflow originates in medullary region and innervates eye, lacrimal and salivary glands and organs in thoracic cavity

2. sacral outflow innervates pelvic and abdominal viscera via nerves called nervi erigentes

Where are most parasympathetic neurons located in?

in their target organs

What are the principal neurotransmitters?

Acetylcholine and Noradrenaline

Preganglionic neurons are _______, and release ____ to act on ______ receptors

1. cholinergic (use ACh as primary transmitter)

2. acetylcholine

3. nicotinic

postganglionic parasympathetic neurons release _____ to act on ______ receptors

1. acetylcholine

2. muscarinic

postganglionic sympathetic neurons release _____ to act on __________ receptors

1. noradrenaline

2. alpha and beta adrenoreceptors

exceptionally, sympathetic neurons innervating ________, release _____ on _______ receptors instead

1. sweat glands

2. acetylcholine

3. muscarinic

Can ANS receptors release more than 1 transmitter or modulator?

Yes, called cotransmission

What other neurotransmitters/modulators can ANS neurons cotransmit?

ATP, NO, VIP (Vasoactive Intestinal Polypeptide)

Do neurotransmitters/modulators act/are released the same or at the same time?

no there are different timeframes for action and different release patterns according to impulse patterns

Where are nicotinic receptors located?

located in:

• autonomic ganglia

• neuromuscular junction

• adrenal medulla

• CNS

receptors located in the: autonomic ganglia, neuromuscular junction, adrenal medulla, CNS are…?

nicotinic receptors

what are the three main nicotinic receptor subclasses?

1. CNS

2. muscle

3. ganglionic

what time of receptors are nicotinic receptors?

ligand gated ion channels with similar molecular structure but behave differently pharmacologically

What is the mechanism of nicotinic receptors?

• nicotinic receptors are coupled to cation channels and mediate fast excitatory synaptic transmission

• Binding of ACh opens cation channels, allowing Na+ and K+ to flow, causing rapid excitation.

How many nicotinic receptor subtypes are there and what structure are they?

Five subunits forming receptor-channel complex in pentameric structures
α, Β, γ, δ, ε

Where are muscarinic receptors located?

Located in:

• SM

• cardiac muscle

• glands in periphery

• CNS (motor control, memory)

receptors located in the: SM, cardiac muscle, glands in periphery, CNS (motor control, memory) are…?

muscarinic receptors

What type of receptors are muscarinic receptors?

G-protein coupled receptors

What is the mechanism of muscarinic receptors?

• cause activation of phospholipase C, inhibition of adenylyl cyclase, activation of K+- channels or inhibition of Ca2+

• Binding of ACh activates intracellular signaling pathways (e.g., activating phospholipase C, inhibiting adenylyl cyclase, or affecting ion channels).

What two components make up Acetylcholine?

Choline and Acetyl from Acetyl-CoA

How is ACh synthesised then released?

1. choline taken up into nerve terminal via membrane transporter

2. free choline is acetylated by cytosolic enzyme Choline Acetyltransferase (CAT) which transfers acetyl group from acetyl-CoA

3. ACh is pumpted from cytosol via transport proteins and packaged into synaptic vesicles

4. ACh is released via exocytosis which is triggered by Ca2+ entry into nerve terminal

5. ACh diffuses across synaptic cleft to combine with receptors on postsynaptic membrane

What happens to ACh after being released

• some released ACh is hydrolysed by acetylcholinesterases bound to BM of nerve termine

• others bind to receptors for ~2ms and then dissociate and is rapidly hydrolysed to prevent binding to another receptor

• then recycled

What is the concentration of choline in the plasma vs near the nerve terminal?

in plasma = 10µM

near nerve terminal = 1mM

How can drugs affect ACh release?

• inhibit synthesis:

  • hemicholinium - blocks choline carrier

• inhibit storage:

  • venomous red back spider - disrupts synaptic vesicles and depletes nerve endings of ACh

• Compete with Ca2+ entry:

  • Mg2+ ions, aminoglycosides

• Block active transport of ACh into vesicles:

  • vesamicol

• Inhibit ACh release:

  • botulinum toxin from Clostridium botulinum (anaerobic bacteria) - cleaves proteins involved in exocytosis in nerve membrane progressive parasympathetic and motor paralysis

  • dry mouth, blurred vision, difficulty swallowing, respiratory paralysis

What drug can inhibit ACh synthesis?

hemicholinium - blocks choline carrier

What drug can inhibit ACh storage?

venomous red back spider - disrupts synaptic vesicles and depletes nerve endings of ACh

What drug competes with Ca2+ entry into nerve terminal?

Mg2+ ions and aminoglycosides

what drug blocks the active transport of ACh into vesicles?

vesamicol

what drug inhibits ACh release?

botulinum toxin from Clostridium botulinum - cleaves proteins involved in exocytosis in nerve membrane progressive parasympathetic and motor paralysis

What are the uses of botulinum toxin A?

skeletal muscle spasm, overactive bladder

what does botulinum toxin A cause?

• causes flaccid paralysis of skeletal muscle

• diminished activity of parasympathetic and sympathetic cholinergic nerves

How long does inhibition last for and what side effect may occur from botulinum toxin A?

• lasts several weeks to 3-4 months

• immunoresistance may occur

what drugs are parasympathomimetic drugs?

muscarinic receptor AGONISTS

• Drugs that mimic the effects of ACh at muscarinic receptors.

What chemical groups do muscarinic receptor agonists have?

• quarternary ammonium group (+ve charge)

• ester group (partial -ve charge)

What organs do muscarinic receptor agonists affect?

• eye

• exocrine glands

• cardiovascular

• smooth muscle

• there are central effects as well

how do muscarinic receptor agonists affect the eye?

cause contraction of:

• constrictor pupillae (pupil constriction)

• ciliary muscle (accomodation for near vision)

how do muscarinic receptor agonists affect the exocrine glands?

• stimulation of exocrine glands w increases in sweating, lacrimation, salivation and bronchial secretions

• stimulate HCl prod in stomach

how do muscarinic receptor agonists affect the cardiovascular system?

• cardiac slowing (negative chonotropic effect, M2)

• decreased CO

• reduced force of contraction (negative inotropic effect)

• vasodilation (NO mediated effect, M3)

how do muscarinic receptor agonists affect smooth muscle?

• contraction of SM in:

  • Lung (bronchoconstriction)

  • GI tract (increased peristalsis)

  • bladder (during micturition)

what central effects do muscarinic receptor agonists have?

• tremor

• hypothermia

• increased locomotor activity

• improved cognition

what drugs cause side effects such as:

• abdominal discomfort - vomiting, diarrhoea, intestinal cramps

• bradycardia, hypotension, flushing

• salivation, sweating

• tremor, improved cognition

muscarinic receptor agonists

what drug interations do muscarinic receptor agonists have?

• other muscarinic agonists

• anticholinesterase medications

• ganglion blocking drugs

What are some contraindications for muscarinic receptor agonists?

• hypersensitivity, parkinsons disease, asthma, epilepsy, vagotonia, hypotension, severe bradycardia

• coronary artery disease

• GI obstruction

• urinary obstruction

• hyperthyroidism

• peptic ulcer

what two cholinesterases are there

1. acetylcholinesterases

2. butyrylcholinesterases

Acetylcholinesterases are _____ cholinesterases and butyrylcholinesterases are ______

1. true

2. pseudocholinesterase

where are acetylcholinesterases found/located?

• located in BM of synaptic cleft

• found in cholinergic nerve terminals and RBCs

serine hydrolases have two distinct regions/sites. What are they>

1. anionic site (glutamade residue) - binds choline moiety

2. esteratic site (histidine and serine) - catalytic

where are acetylcholinesterases found/located?

• found in tissues of liver, skin, brain and GI smooth muscle

• plasma

which cholinesterase demonstrates narrow substrate specificity (primary ACh)

acetylcholinesterases

which cholinesterases exert broad substrate specificity

butyrylcholinesterases

What is a short acting anticholinesterase and how long does it last?

Edrophonium - 2 min duration

What is a medium duration anticholinesterase and how long does it last for?

Neostigmine and Physostigmine - 3 hour duration

What anticholinesterases are irreversible?

organophosphates

what are some examples of irreversible anticholinesterases?

• nsecticides - parathion

• therapeutic uses - ecothiopate

• chemical warfare - sarin

• common drug for poisons and suicide

What drug can reactivate cholinesterases?

Pralidoxime

How does pralidoxime reactivate cholinesterases ?

• brings oxime grp close to phosphorylated esteratic site

• attracts phophate grp from serine hydroxyl grp

What effects do anticholinesterases have in autonomic cholinergic synapses?

• increased ACh @ nerve terminals

• increased secretions

• increased peristaltic activity

• bronchoconstriction

• bradycardia and hypotension

• pupillary constriction

• fixation of accommodation for near vision

• decreased intraocular pressure

What are some clinical uses of anticholinesterases?

• anaesthesia: neostigmine reverses effects of non-depolarising neuromuscular blocking drugs

• glaucoma: ecothiopate

• alzheimers: tacrine, donepezil, galantamine, rivastigmine

• myasthenia gravis: neostigmine

What type of drugs can be used for anaesthesia, glaucoma, alzheimers and myasthenia gravis

anticholinesterases

What chemical groups are muscarinic receptor antagonists composed of?

ester and basic groups

• tertiary ammonium compounds

• quarternary ammonium compounds

what organs do muscarinic receptor antagonists affect?

• exocrine secretions

• heart rate

• eye

• GI tract

• SM

• CNS

What effect does muscarinic receptor antagonists have on exocrine secretions?

decreased secretions of salivary, lacrimal, bronchial, and sweat glands

What effect does muscarinic receptor antagonists have on heart rate

tachycardia

What effect does muscarinic receptor antagonists have on the eye

• pupil dilation (mydriasis)

• paralysis of accommodation (cycloplegia)

What effect does muscarinic receptor antagonists have on the GI tract

inhibition of GI motility

What effect does muscarinic receptor antagonists have on SM

relaxation of bronchial, biliary and urinary SM

What effect does muscarinic receptor antagonists have on CNS

• antiemetic effects and treating motion sickness - hyoscine

• reduce involuntary movement's in parkinson’s disease by inhibiting extrapyramidal system

• reduced cognition/arousal

Muscarinic antagonists have clinical uses for:

• sinus bradycardia

• ophthalmic - dilate pupil

• prevention of motion sickness

• parkinsonism

• asthma

• anaesthetic premedication

• GI endoscopy antispasmotic - IBS, colonic diverticular disease

• Peptic ulcer - reduce acid secretion via M$_3$ receptors

What are some contraindications for muscarinic receptor antagonists?

• hypersensitivity

• myasthenia gravis

• severe cardiac disease

• GI obstructive disease

• narrow-angle glaucoma

• acute haemorrhage

• prostatic hypertrophy

• urinary retention

• pyloric obstruction

• ulcerative colitis

• toxaemia

• febrile condition

What is an example of ganglionic nicotinic receptor agonists?

• dimethylphenylpiperazinium (DMPP) - no therapeutic value

• nicotine is provided in (DMPP) - no therapeutic value

• nicotine is provided in patches and gum for relief from cigarette smoking

What is an example of ganglionic nicotinic receptor antagonists/ganglion blocking drugs?

hexamethonium, nicotine (high doses)

What do ganglion blocking drugs/nicotinic receptor antagonists do?

• interfere w ACh release

• prolonged depolarisation causing desensitisation