Organisation of the nervous system

Neuron

Cell body (with the nucleus), dendrites, axon (with a myelin sheath) and terminal bulb.

Synapse

The junction between a presynaptic and a postsynaptic neuron, across the synaptic cleft; neurotransmitters carry the signal across.

Somatic vs autonomic signalling

Nerve type, ganglionic neurotransmitter, and effector-organ neurotransmitter

The sympathetic and parasympathetic systems work in an opposing manner, and so maintain the balance of involuntary function. Broadly: sympathetic → a stressful (“fight or flight”) situation; parasympathetic → rest.

Sympathetic and parasympathetic divisions

Effects on target organs

Neurohumoral transmission

Nerves transmit a message across synapses and neuroeffector junctions by the release of a humoral (chemical) messenger. There are five steps in neurohumoral transmission.

1. 1. Impulse conduction

   At rest, the node of Ranvier holds a resting potential of about –70 mV (K⁺ inside, Na⁺/Cl⁻ outside). Depolarisation: Phase 1 — voltage-sensitive Na⁺ channels open; Phase 2 — K⁺ channels open with a delay, terminating the depolarisation. This generates a local circuit current, which activates the next excitable part of the membrane, propagating the action potential along the membrane. Note: tetrodotoxin (from puffer fish) and saxitoxin (from certain shellfish) selectively abolish Na⁺ conductance in the nerve fibre, blocking impulse conduction.

2. 2. Transmitter release

   The nerve impulse causes fusion of the vesicular and axonal membrane through Ca²⁺ entry, which fluidises the membrane; the transmitter is then extruded from the vesicles by exocytosis. Note: this release process can be modulated by the transmitter itself, or by other agents, acting through specific receptors located on the prejunctional membrane.

3. 3. Transmitter action on the postjunctional membrane

   The transmitter binds specific receptors at the postjunctional membrane, producing either an excitatory postsynaptic potential (EPSP) — an increase in permeability to cations, causing Na⁺ or Ca²⁺ influx and depolarisation — or an inhibitory postsynaptic potential (IPSP) — an increase in permeability to anions, causing Cl⁻ to move in and hyperpolarise the membrane (K⁺ efflux also contributes).

4. 4. Postjunctional activity

   An EPSP produces a postjunctional action potential — a nerve impulse in a neuron, contraction in a muscle, or secretion in a gland. An IPSP stabilises the postjunctional membrane, so it resists depolarising stimuli.

5. 5. Termination of transmitter action

   Parasympathetic neurone: ACh is hydrolysed by acetylcholinesterase (AChE). Sympathetic neurone: noradrenaline is largely taken back into the neuron by the membrane-bound noradrenaline transporter (NET) and recycled; a minor fraction diffuses away. GABAergic neurone: released GABA is partly taken up into the neuron by the GABA transporter (GAT) and into neighbouring glial cells; some GABA is dissipated by diffusion.

Co-transmission and classification of neurotransmitters

Co-transmission

• On stimulation, most peripheral and central neurons release more than one active substance.
• In the ANS, besides ACh and noradrenaline, purines (ATP, adenosine), peptides, nitric oxide and prostaglandins are also released as co-transmitters.
• Function: (i) a co-transmitter may regulate the presynaptic release of the primary transmitter and/or postsynaptic sensitivity to it; (ii) it may act as an alternative transmitter in its own right and/or exert a trophic influence on synaptic structure.
• The time-course of action of the primary transmitter and its co-transmitter(s) is usually different.

Classification of neurotransmitters in the PNS

Adrenergic (noradrenaline) and cholinergic (acetylcholine) are the two classical neurotransmitters of the PNS. In the somatic efferent system, ACh acts on nicotinic (N) receptors at skeletal muscle. In the sympathetic system, ACh acts on nicotinic ganglionic receptors, and the postganglionic fibre releases noradrenaline (acting on α/β receptors) — except at sweat glands and some skeletal-muscle blood vessels, where the postganglionic fibre is cholinergic (releases ACh), and at the adrenal medulla, which is innervated directly by a preganglionic cholinergic fibre and secretes catecholamines into the blood. In the parasympathetic system, ACh acts at the ganglion (nicotinic) and again at the effector organ (muscarinic, M).

Non-peptide NANC transmitters

Peptide NANC transmitters

Parasympathomimetics: synthesis, storage and release of ACh

Parasympathomimetics (cholinomimetic / cholinergic drugs) mimic the parasympathetic nervous system by releasing (or acting like) acetylcholine. A cholinergic drug is called a cholinomimetic, and acts on both muscarinic and nicotinic receptors.

• ACh acts on both post-synaptic and pre-synaptic receptors.
• ACh is hygroscopic and has a short half-life.
• Blockers along this pathway: hemicholinium blocks the choline transporter; vesamicol blocks the vesicular ACh transporter; botulinum toxin blocks vesicle fusion / exocytosis.

Cholinoreceptors

Muscarinic receptors are G-protein-coupled receptors (a rosette-like pentameric structure) with major subtypes M₁, M₂, M₃ and minor subtypes M₄, M₅. Nicotinic receptors are ligand-gated ion channels, with subtypes Nₘ (neuromuscular) and Nₙ (ganglionic / CNS).

Muscarinic agonist: muscarine. Muscarinic antagonist: atropine.

Nicotinic agonist: nicotine. Nicotinic antagonist: tubocurarine / hexamethonium.

Cholinergic drug classification and the prototype (acetylcholine)

Prototype: acetylcholine (direct-acting)

Structure

A permanently charged quaternary ammonium group.

Absorption / distribution

Poorly absorbed and distributed in the CNS, due to its hydrophilic nature. A large amount must be infused intravenously to achieve a concentration sufficient to produce a detectable effect. Intramuscular and subcutaneous injection produce only local effects.

Metabolism / excretion

Metabolised in the liver and excreted chiefly by the kidney.

Mechanism of action — muscarinic action

• Eye: miosis — contraction of the smooth muscle of the iris sphincter.
• CVS: reduction in peripheral vascular resistance and changes in heart rate — vasodilation results in reduced BP and heart rate.
• GIT: increases peristaltic movements and GI secretions; relaxes the sphincter (may cause defecation).
• Urinary bladder: contracts the muscle; relaxes the trigone and sphincter (causes urination).
• Bronchi: contracts bronchial smooth muscle; increases secretion.

Mechanism of action — nicotinic action

• Autonomic ganglia: tachycardia and raised BP.
• Skeletal muscle: twitching and fasciculation, followed by prolonged depolarisation and paralysis.
• CNS: given intravenously, ACh does not cause any central effect, as it cannot pass through the blood–brain barrier.

Uses: choline esters are rarely used clinically. ACh itself is not used because of its evanescent (very short) and non-selective action.

Indirect-acting agents (anticholinesterases)

Chemistry: carbamates are esters of carbamic acid; organophosphates are derivatives of phosphoric acid.

Pharmacokinetics (physostigmine)

• Rapidly absorbed from the GIT and parenteral sites.
• Applied to the eye, it penetrates the cornea freely.
• Crosses the blood–brain barrier.
• Disposed of after hydrolysis by cholinesterase.

Mechanism of action

Carbamates and phosphates react with the esteratic site of the enzyme, carbamylating and phosphorylating it; the reaction is extremely slow to reverse, so these do not react with water. The half-life of reactivation of the carbamylated enzyme is less than the time it takes to synthesise fresh enzyme protein, while that of the phosphorylated enzyme is longer than the regeneration time.

Organ system effects

• CNS: at low concentration, diffuse activation on the EEG and a subjective alerting response; at high concentration, generalised convulsions may be followed by coma and respiratory arrest.
• Eye, respiratory tract, GIT, urinary tract: similar to the direct-acting agents above.
• CVS: moderate doses give a modest bradycardia, a fall in cardiac output, and increased vascular resistance (raising BP); at high concentration, marked bradycardia, a significant fall in cardiac output, and hypotension.
• Neuromuscular junction: at low concentration, prolongs and intensifies the action of physiologically released ACh, increasing the strength of contraction — especially in muscle weakened by curare-like neuromuscular blocking agents or by myasthenia gravis. At high concentration, accumulation of ACh results in fibrillation of muscle fibres and antidromic firing of the motor neuron.
• Some quaternary carbamate cholinesterase inhibitors, e.g. neostigmine, have an additional direct nicotinic agonist effect at the neuromuscular junction — making them effective agents for myasthenia gravis therapy.

Uses: (1) as a miotic; (2) myasthenia gravis.

Parasympatholytics: classification

Parasympatholytics (anti-cholinergic drugs) are cholinergic antagonists that act on muscarinic receptors and block them — also called antimuscarinic agents, anticholinergic drugs, or atropine-like drugs. They are competitive antagonists.

Prototype: atropine

Structure

A naturally occurring tertiary-amine alkaloid, an ester of tropic acid. Found in the plants Atropa belladonna and Datura stramonium. Has an anti-muscarinic effect. Tertiary members of this class are often used for their effect on the eye or the CNS; quaternary amine antimuscarinic agents have been developed to produce more peripheral effect and reduced CNS effect.

Absorption

Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes; when applied in a suitable vehicle, some are even absorbed across the skin (transdermal).

Distribution

Reaches a significant level in the CNS within 30–60 minutes. Quaternary derivatives are poorly taken up by the brain.

Metabolism / excretion

Elimination of atropine from the blood occurs in two phases: the rapid phase has a half-life of about 2 hours, the slow phase about 13 hours. About 60% of the drug is excreted unchanged in the urine. Effects on the iris and ciliary muscles persist for ≥72 hours.

Mechanism of action

A competitive antagonist at all muscarinic receptor subtypes; the antagonism can be overcome by raising the concentration of ACh at the receptor site of the effector organ. Recent evidence indicates that muscarinic receptors are constitutively active, and most drugs that block the action of acetylcholine — including atropine — are inverse agonists that shift the equilibrium to the inactive state of the receptor. The receptors antagonised by atropine are the peripheral structures that are normally stimulated or inhibited by muscarine.

Organ-system-specific effects

CNS

Minimal stimulant effect, especially on the parasympathetic medullary centres, and a slow, long-lasting sedative effect on the brain. The tremor of Parkinson’s disease is reduced; often effective at preventing or reversing muscarinic cholinergic transmission.

Eye

Mydriasis (dilated pupils); weakens contraction of the ciliary muscles (cycloplegia), so a fully atropinised eye cannot focus on near vision. Reduces lacrimal secretion, causing dry eyes.

CVS

Tachycardia at moderate–high dose; initial bradycardia at low dose. Reduces the PR interval of the ECG. Atropine blocks vasodilation due to parasympathetic nerve stimulation and to sympathetic cholinergic nerves; it has little effect on BP overall.

Respiratory

Bronchodilation and reduced secretion — used in the treatment of COPD or asthma. Atropine (and other antimuscarinic drugs) is used before administering an inhalant anaesthetic, to reduce the accumulation of secretion in the trachea.

GIT

Dry mouth; at large doses, gastric secretion is blocked; reduces motility (gastric emptying is prolonged and intestinal transit time is lengthened).

Genitourinary

Relaxes the smooth muscle of the uterus and bladder wall.

Sweat glands

Atropine suppresses thermoregulatory sweating.

Sympathomimetics: synthesis and storage of catecholamines

The classic catecholamine neurotransmitters (noradrenaline, and adrenaline from the adrenal medulla) are synthesised in the nerve terminal from tyrosine.

Tyrosine is transported into the nerve terminal by a Na⁺-dependent transporter; metyrosine inhibits tyrosine hydroxylase, the first and rate-limiting step. Once made, noradrenaline is stored in vesicles by the vesicular monoamine transporter (VMAT), which reserpine blocks. Ca²⁺ entry triggers exocytotic release (blocked by bretylium and guanethidine). Released noradrenaline acts on postsynaptic adrenoceptors and other receptors, and is largely taken back up into the neuron by the noradrenaline transporter (NET) — blocked by cocaine and tricyclic antidepressants. Presynaptic autoreceptors and heteroreceptors modulate further release.

Adrenoceptors: subtypes and mechanism of action

Adrenoceptors are membrane-bound, G-protein-coupled receptors. They function primarily by increasing or decreasing the intracellular production of the second messengers cAMP or IP₃/DAG. In some cases the activated G-protein itself operates a K⁺ or Ca²⁺ channel, or increases prostaglandin production.

α receptors

Selective agonist / antagonist — α₁: phenylephrine / prazosin. α₂: clonidine / yohimbine.

β receptors

Selective agonist / antagonist — β₁: dobutamine / metoprolol, atenolol. β₂: salbutamol, terbutaline / α-methylpropranolol. β₃: mirabegron / CGP20712A, ICI118551.

A little more mechanistic detail

α1, in smooth muscle

Activated Gq protein → raised IP₃/DAG production → mobilisation of Ca²⁺ from intracellular organelles → activation of calmodulin-dependent myosin light-chain kinase → phosphorylation of myosin → contraction.

α2, vascular

Vasoconstriction: α2 receptors enhance Ca²⁺ influx without utilising IP₃.

α2, prejunctional

Activates the Gi protein, which inhibits neural Ca²⁺ channels (reducing NA release) and lowers cAMP, limiting the intracellular availability of Ca²⁺ — NA release is diminished. G-protein-gated K⁺ channel activation also causes hyperpolarisation.

α2, in the gut

α2 receptor activation hyperpolarises cholinergic neurons, reducing ACh release and so reducing gut tone; α1 receptor activation increases K⁺ efflux (via Ca²⁺-dependent K⁺ channels), causing hyperpolarisation and relaxation.

α2, in pancreatic β cells

Stimulation reduces cAMP formation, decreasing insulin release.

β action (adrenaline)

Activates the Gs protein → activates adenylyl cyclase → ATP is broken down to cAMP → phosphorylates intracellular cAMP-dependent protein kinases → initiates a series of reactions: in liver and muscle, glycogen phosphorylase is activated (glycogenolysis) and glycogen synthase is inhibited, causing hyperglycaemia; in adipose tissue, triglyceride lipase is activated, raising plasma free fatty acids and increasing O₂ consumption and heat production; in the heart, troponin and phospholamban are phosphorylated — troponin phosphorylation increases the interaction with Ca²⁺ at the myofilaments, increasing the force of contraction, while phospholamban phosphorylation causes sequestration of Ca²⁺ by the sarcoplasmic reticulum, giving more rapid relaxation; in gut and bronchial muscle, relaxation is induced; in the pancreatic islets, β2-receptor activation (via raised cAMP) increases glucagon secretion from α cells and increases insulin secretion from β cells.

Sympathomimetics: classification, uses and adverse effects

By spectrum of activity

• α agonists: α₁-selective — phenylephrine; α₂-selective — clonidine
• β agonists: non-selective — isoprenaline; β₂-selective — terbutaline, salbutamol; β₁-selective — dobutamine
• α and β agonist: adrenaline, noradrenaline
• Dopamine agonist: dopamine, fenoldopam

Therapeutic classification

Prototype: adrenaline

Structure

A β-phenylethylamine, with substitution on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group.

Absorption / distribution

IV injection disappears rapidly from the bloodstream. SC or IM injection gives a rapid onset and short duration of action. Given subcutaneously during an asthmatic attack, it may produce bronchodilation within 5–10 minutes, with maximal effect within 20 minutes.

Metabolism

Rapidly inactivated, mainly by enzymatic transformation to metanephrine or normetanephrine, either of which is then conjugated and excreted in the urine. Inactivated by the enzymes COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase).

Elimination

Through the urine, as sulfate and glucuronide conjugates of its metabolites. Only a small amount of the drug is excreted completely unchanged.

Sympatholytics (adrenergic blocking drugs)

α-adrenergic blocking drugs

β-adrenergic blocking drugs