Topic 2.7: Neuromuscular system - Autonomic pharmacology

pros and cons of targeting ANS

Targeting the ANS has potential to alter variety of tissue/ organ functions

Benefit: wide therapeutic opportunity

Concern: great potential for adverse effects -> eg. off target tissue effects

primary neurotransmitters responsible for communication within particular division - neurotransmitter list (2)

acetylcholine

noradrenaline

primary neurotransmitters responsible for communication within particular division - somatic

Acetylcholine released from somatic motor neurons and act on nicotinic cholinoceptors

primary neurotransmitters responsible for communication within particular division - parasympathetic

Acetylcholine for ganglionic transmission via nicotinic cholinoceptors

Acetylcholine released from parasympathetic motor neurons and act on muscarinic cholinoceptors

primary neurotransmitters responsible for communication within particular division - sympathetic (3)

Noradrenaline for sympathetic nerves → activation of adrenoreceptors

Acetylcholine released from post-ganglionic sympathetic neurons at sweat glands/ adrenals -> muscarinic cholinoceptors

adrenaline from adrenal gland → adrenoceptors

types of cholinergic recetpros (2)

muscarinic → post-parasympatheitc and post-symapthtic at sweat glands

nicotinic → somatic, ganglionic transmission

steps in chemical transmission that are used as sites of drug action (3)

release

re-uptake

degradation

neurotrransmitter release - steps (3)

1. Vesicle docks at active zone -> synaptobrevin forms SNARE complex with target SNAREs which brings vesicle close to plasma membrane 

1. Increase in calcium concentration sensed by synaptotagmin found on vesicle membrane

2. Calcium bound synaptotagmin triggers membrane fusion leading to neurotransmitter release

drug that targets release of neurotransmitter

botulinum

drug that targets reuptake and degradation of neurotransmitter

cocaine

Pseudoephedrine

neostigmine

botulinum toxin - method (3)

1. Heavy chain binds with high affinity to specific receptors on membrane of terminals containing Ach -> selectively inhibits cholinergic transmission

2. Cleaves specific SNARE proteins to prevent SNARE complex from forming -> no vesicular fusion

3. Muscle fibre is paralysed

botulinum toxin - poisoning summary

caused by C. botulinum → anaerobic bacteria

causes progressive motor paralysis with varying degrees of muscle weakness

botulinum toxin - symptom of poisoning (5)

• Difficulty swallowing

• Facial weakness -> droopy eyelids and hanging jaw

• Trouble talking

• Limb paralysis

• May progress to respiratory paralysis

botulinum toxin - medical uses (4)

can inhibit parasympathetic effects → anti SLUD

• dry eyes

• dry mouth

• urinary retention

• constipation

SLUD

salivation

lacrimation

urination

defecation

botulinum toxin - cosmetic use

Paralyses superficial muscle that pucker the skin (local injection) by preventing Ach release at neurons for superficial muscles

botulinum toxin - clinical uses (3)

• Unwanted movement disorders

• Urinary incontinence associated with bladder overactivity

• Hyperhidrosis -> excessive sweating

predominate method to inactivate sympathetic neurotransmission

target reuptake

neurotransmitter reuptake - process summary (4)

Primary process = neuronal uptake via high affinity noradrenaline transporter (NET)

Secondary process = extra neuronal uptake via low-affinity organic cation transporter (OCT3)

After reuptake, noradrenaline is transported into vesicle via vesicular monoamine transporter for re-release

If not taken up by synaptic vesicle: metabolised by monoamine oxidase (MAO) in nerve terminal or COMT in non-neuronal tissue 

targeting reuptake - cocaine

inhibits NET and thus re-uptake of noradrenaline

Greater concentration of noradrenaline in junction and longer presence in junction = more noradrenaline to bind and activate post-junctional adrenoreceptors

targeting reuptake - indirect acting sympathomimetics (IAS) summary (3)

can mimic tissue responses observed in sympathetic activation

Structurally similar to noradrenaline -> calcium independent noradrenaline release

Because IAS is structurally similar to noradrenaline, could potentially be metabolised by MAO -> limit noradrenaline metabolism

targeting reuptake - indirect acting sympathomimetics (IAS) steps (4)

1. IAS can be transported by NET into nerve terminal

2. IAS transported into vesicles by VMAT in exchange for noradrenaline -> noradrenaline displaced into cytosol

3. Displaced cytosolic noradrenaline enters junction via NET

4. Noradrenaline activates post-junctional adrenoceptors -> IAS are sympathomimetic

targeting degradation - ACh metabolism summary (2)

Acetylcholinesterase (AChE) can rapidly metabolise ACh into choline and acetic acid -> can be take up into presynaptic cell where choline can be incorporated into new ACh

Anticholinesterases (acetylcholinesterase inhibitors) can inhibit AChE`

targeting degradation - Myasthenia Gravis on NMJ function without neostigmine (3)

Autoantibodies block and target nAChRs for degradation → less nAChR available to bind to Ach

Most Ach rapidly degraded before sufficient receptors activated

Only a weak EPP generated (not enough for threshold)-> leads to muscle weakness

targeting degradation - Myasthenia Gravis on NMJ function with neostigmine (3)

1. Neostigmine prevents ACh metabolism -> reversible anti-cholinesterase

2. Enables lateral diffusion of ACh to bind unaffected nAChRs and rebinding of ACh to multiple nAChRs

3. Restores cholinergic transmission in NMJ leading to symptomatic improvement

distribution of adrenoceptors

Different types of adrenoceptors control different biochemical pathways and thus different physiological pathways

tissues differ in adrenoceptor expression profiles

adrenoceptor types and associated G protein alpha subunit isoform- list (4)

• alpha 1 → Ga_q

• alpha 2 → Ga_i

• beta 1 → Ga_s

• beta 2 → Ga_s

adrenoceptor types - alpha 1 activity steps (4)

1. Activation of receptor results in activation of the membrane bound enzyme - phospholipase C

2. Phospholipase-C is responsible for conversion of phospholipids into second messengers (IP3 and DAG)

3. IP3 can stimulate released of calcium from intracellular stores

4. Increase in intracellular calcium results in smooth muscle contraction

adrenoceptor types - alpha 2 activity steps (3)

1. Activation of receptor results in inhibition of adenylate cyclase

2. Decreased cAMP production

3. Decreased cAMP concentration decreases neurotransmitter release

adrenoceptor types - beta 1 activity steps (3)

1. Activation of receptor results in activation of adenylate cyclase

2. Adenylate cyclase produces cAMP

3. Increased cAMP concentration result in increased contractile rate in the heart and renin release in kidney

adrenoceptor types - beta 1 activity steps (3)

1. Activation of receptor results in activation of adenylate cyclase

2. Adenylate cyclase produces cAMP

3. Increased cAMP concentration results in smooth muscle relaxation

adrenoceptor types - responses list (4)

• alpha 1 → smooth muscle contraction

• alpha 2 → decreased neurotransmitter release

• beta 1 → increased contractile rate/ force of heart and renin release of kidney

• beta 2 → smooth muscle relaxation

muscarinic cholinergic receptors - types and location found (2)

M2 = expressed in sinoatrial node

M3 = found on smooth muscle and various glands

muscarinic cholinergic receptors - M2 (2)

Activation by acetylcholine or another agonist causes a decrease in heart rate

Related to Ga_i -> inhibition of adenylate cyclase and decreased cAMP

muscarinic cholinergic receptors - M3 (2)

Activation results in increased gastric and salivary secretion, and smooth muscle contraction

related to Ga_q → stimulation of PLC and increased IP3 and DAG

nicotinic cholinergic receptors - types and location found (2)

N1 = in neuromuscular junction

N2 = in autonomic ganglia

differ in subunit compositions

nicotinic cholinergic receptors - consequence of different subunit compositions

differences in:

• Cation permeability

• Physiological function

• Pharmacological properties

nicotinic cholinergic receptors - N1 and N2 differences in pharmacological properties example

N1: D-tubocurarine = nAChR antagonist for NMJ → used as msucle relaxant in anaesthesia

N2: Hexamethonium = nAChR antagonist for autonomic ganglia → inhibit activation of heart and vlood vessels in hypertension

nicotinic cholinergic receptors - D-tubocurarine summary (3)

competitive reversible nicotinic receptor antagonist

selectively targets NMJ but also autonomic ganglia at high concentrations

can have adverse effects, including hypotension due to ganglion-block -> replaced with drugs that are less effective at autonomic ganglia

nicotinic cholinergic receptors - hexamethonium summary (4)

used as anti-hypertensive agent

Hexamethonium can inhibit ganglionic transmission  -> sympathetic-mediated activation of heart and blood vessels inhibited

Nicotinic receptors = responsible for sympathetic transmission in both parasympathetic and sympathetic nervous system -> can also decreased parasympathetic outflow

More risk than benefits

nicotinic cholinergic receptors - example for achieving selective therapy an better risk-benefit ratios

Hexamethonium used as anti-hypertensive agent → beta adrenoceptor antagonist → beta-1 adrenoceptor antagonist

Hexamethonium also decreased parasympathetic outflow

beta adrenoreceptor also inhibits smooth muscle relaxation and lipid soluble so crossed blood-brain barrier to cause dreams and insomnia

beta-1 adrenoceptor = cardio selective, hydrophilic → minimal adverse effects

how to achieve selective therapy and better risk benefit ratios (2)

1. Exploit:

• Different neurotransmitters and thus pathways of synthesis

• Different mechanisms for inactivating neurotransmitter responses

• Different receptors and subtypes of receptors

• Different receptor expression on tissues

2. Restrict site of drug administration