Autonomic Nervous System

• Agonist: a chemical that activates a receptor to produce a biological response.
• Antagonist: a chemical or ligand that blocks or dampens a biological response by binding to the receptor rather than activating.
• Partial agonist: chemicals that bind to and activate a given receptor, but only have partial efficacy relative to a full agonist.
• Efficacy: the maximum response achievable from an applied or dosed agent.
• Inverse agonist: a chemical that binds to the same receptor as an agonist but gives a pharmacological response opposite to that of the agonist.
• Contraction of a muscle can be done via:

  • Stimulation of a nerve
  • Nicotine
  • Stimulation of a muscle
• Receptors are typically present in low concentrations and show saturable binding.

  • Can be presented in a graph of drug bound vs drug concentration
  • Many drugs have high affinities for their receptors and will bind at low concentrations
• Receptors have a binding site complementary to a drug, with agonists inducing conformational changes in their receptors.

  • Antagonists do not induce conformational change
  • In dopamine receptors (TM3) there is an aspartate residue with a negative charge
  • Introducing another amino acid that is not negatively charged will cause dopamine to not bind
• Drug-receptor interactions are usually fully reversible with the exception of toxins and phenoxybenzamine (irreversible antagonist that reduces blood pressure by binding to alpha-adrenoceptors).
• Drugs are typically small molecules (MW < 200) where the receptor is a lot larger (MW > 250,000). There are two binding sites for ACh in a nicotinic receptor to allow the channel to open.
• Phenoxybenzamine:

  • Non-competitive antagonist of alpha receptors
  • Used in treatment of hypertension
  • Forms a permanent covalent bond with adrenergic receptors

  
• Hexamethonium:

  • Non-depolarising ganglionic blocker
  • nAChR antagonist in sympathetic and parasympathetic ganglia

  
• The autonomic nervous system:

  • Sympathetic, parasympathetic and enteric
  • Main role is in homeostasis
  • Sympathetic has short preganglionic neuron, parasympathetic has a long preganglionic neuron

  
• The autonomic system is important for:

  • Pupillary dilation
  • Dilation and constriction of blood vessels
  • Heart beat
  • GI movements
  • Gland secretion
  • Energy metabolism (liver and skeletal muscle)
• Ganglion: a group of nerve cell bodies that lie outside the CNS. This is the point of contact between the first and second efferent neurone in the pathway.
• Amygdala: main limbic region for emotions
• Hypothalamus: main integration centre
• Reticular formation: most direct influence over autonomic function
• Exceptions to the sympathetic nervous system:

  • Kidneys: postganglionic neurons to smooth muscle of the renal vascular bed release dopamine
  • Adrenal gland: preganglionic neurons do not synapse in the paravertebral sympathetic ganglion. Postganglionic neurons synapse directly on the adrenal gland, release ACh and activate nicotinic receptors on the adrenal gland - these then release epinephrine into systemic circulation
• Neurotransmission in the ANS:

  1. Excitatory transmission at all autonomic ganglia, sympathetic or parasympathetic, involves ACh acting on nicotinic choline receptors
  2. Transmission at the postganglionic sympathetic synapse usually involves noradrenaline acting on either alpha or beta adrenoceptors
  3. Transmission at the postganglionic parasympathetic synapse usually involved in ACh acting on muscarinic receptors

  
• Sympathetic and parasympathetic inputs are often antagonistic e.g., sympathetic dilates pupil, parasympathetic constricts pupil.
• The enteric nervous system:

  • Myenteric plexus allows for forward inhibition and excitation
  • Each system (sympathetic/parasympathetic) can signal either directly or indirectly using the myenteric plexus
  • Consists of neurons that regulate GI tract
  • Expresses mechanoreceptors and chemoreceptors that are involved in local reflex pathways that regulate the activity of the gut independent of neural input

  
• Dysautonomia: a condition resulting from damage to the autonomic nerves. Symptoms include problems with sweating, heart rate control, hypotension, vision etc.
• Sympathetic organ synapses:

  • Adrenaline mimics sympathetic nerve stimulation
  • The Finkelman preparation provided evidence that the sympathetic nervous system releases an adrenaline like compound

  
• Noradrenaline is the main transmitter in the postganglionic synapse, except for sweat glands (ACh), resistance blood vessels in skeletal muscle, and other neurotransmitters (NANC - non-adrenergic, non-cholinergic).

  
• The dopamine synthetic pathway:

  • Tyrosine to L-DOPA by tyrosine hydroxylase
  • L-DOPA to dopamine by DOPAdecarboxylase
  • Dopamine to noradrenaline by dopaminebetahydroxylase
  • Noradrenaline to adrenaline by phenylethanolamine N-methyltransferase (PNMT)

  
• False neurotransmitters:

  • Tyramine (increases blood pressure)
  • Octopamine (displaces noradrenaline from vesicles)
  • Synephrine

  
• Alpha-methyltyrosine: competitive inhibitor of tyrosine hydroxylase used in treatment of phaeochromocytoma (benign tumour of the adrenal medulla of chromaffin cells).

  
• Alpha-methyl DOPA: a drug used to interfere with NAdr transmission as it leads to the synthesis of false transmitter alpha-methyl-NAdr.

  
• Carbidopa: inhibits DOPA decarboxylase and is used in the treatment of Parkinson's disease. It is co-administered with DOPA to stop peripheral metabolism of L-DOPA and does not cross the BBB.

  
• Noradrenaline is stored in vesicles, moved by a transport mechanism driven by a proton gradient, stored with ATP and chromogranin.

  • Interfered by antihypertensives such as guanethidine, reserpine and rauwolfia
  • Side effects include depression (r) or orthostatic hypotension (g)

  
• Uptake of noradrenaline - uptake 1:

  • NAT (noradrenaline transporter)
  • High affinity, low capacity, present on nerve terminal
  • Requires Na+ gradient and ATP
  • Blocked by antidepressants (imipramine, amitriptyline, desipramine) and cocaine
  • Stimulated by indirect sympathomimetics/psychostimulants (tryptamine, ephedrine and amphetamine)
• Uptake of noradrenaline - uptake 2:

  • Low affinity, high capacity, present on extraneuronal tissue
  • Inhibited by cortisol
• Monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) have the major metabolites of 3-methoxy-4-hydromandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG).

  • Plasma levels of these metabolites can be useful biomarkers of disease
  • Monoamine oxidase inhibitors (MAOIs) interfere with NAdr metabolism such as Iproniazid

  
• Alpha adrenoceptors:

  • Predominantly postsynaptic
  • Feedback inhibition of neurotransmitter release at the synapse mediated by alpha 2
• Alpha agonists:

  • Phenylephrine: 1 > 2
  • Methoxamine: 1
  • Clonidine: 2 (anihypertensive)
• Alpha antagonists:

  • Phentolamine: 1 = 2
  • Phenoxybenzamine: 1 (antihypertensive)
  • Prazosin: 1 > 2
  • Yohimbine: 2 > 1 (slight inhibition of NAdr binding)
• Beta adrenoceptors:

  • Predominantly presynaptic
  • All GCPRs and stimulate cAMP formation
• Beta agonists:

  • Isoprenaline: 1 > 2
  • Salbutamol: 2 > 1
  • Dobutamine: 1 > 2
• Beta antagonists:

  • Propranolol: non selective (antihypertensive)
  • Atenolol: 1