Session 9 Pharmacology of ANS, receptor regulation

• Sympathetic system: Preganglionic neurons release acetylcholine, postganglionic neuron releases noradrenaline.
• Parasympathetic system: Preganglionic neurons release acetylcholine, postganglionic neuron releases acetylcholine.
• α1 antagonists- eg prazosin -are given to reduce blood critically high pressure. (but cause postural hypotension).
• α1 antagonists eg alfuzosin are also given to older men to relax the muscles in the prostate and bladder neck, making it easier to urinate. It is thus used to treat benign prostatic hyperplasia.
• α2 agonists -eg clonidine- are also given to lower blood pressure as they inhibit noradrenaline release.
• Noradrenaline acts mainly on adrenergic α-receptors.
• Adrenaline acts mainly on beta-receptors.
• Beta 1 blockers (eg atenolol) -are given to reduce heart rate & force in stressed or hypertensive patients. Side effects are bronchoconstriction.
• Beta 2 agonists (eg salbutamol)- are given to relax bronchial smooth muscle in asthmatics.
• Beta 3 agonists (eg mirabegron) are given to prevent bladder spasm and excessive urinary urge.
• Both neurones in the parasympathetic outflow are cholinergic. The first synapse is nicotinic, like the sympathetic system. The second neurone acts on muscarnic.
• • After binding to the receptor the ACh is released from its binding site and re-enters the synaptic cleft.
  • It can then bind to acetylcholinesterase. These break down the acetylcholine to choline and acetic acid.
  • The choline is taken back up into the axon by uptake pumps to be recycled into ACh by choline acetylase.
• Non-competitive antagonist : Binds to a different site, inducing conformational change which alters the ability of receptor to bind agonist
• Signal Transduction Mechanisms for Agonists?

  • Direct activation of an ion channel
  • G-protein activation of an ion channel
  • G-protein activation of a second messenger system
  • Receptor activation of an intracellular enzyme (e.g. tyrosine kinase).
• Super/Hypersensitivity - refers to an enhanced response to an agonist. Hypersensitivity may occur as a result of unmasking of receptors or accentuation of signal amplification.
• Synergism - when two receptors produce a combined effect that is greater than the sum of their individual effect.
• Upregulation - refers to an increase in the number of receptors due to prolonged deprivation of receptors of interacting with their physiological neurotransmitter (e.g. by denervation of chronic use of a receptor antagonist). By expressing more receptors, there is a greater probability that a hormone will bump into and stimulate its receptor.
• Cellular mechanism of increased response?

  • Upregulation
  • Super/hypersensitivity
  • Synergism
• Cellular mechanism of decreased response?

  • Desensitization
  • Downregulation
  • Tachyphylaxis
  • Tolerance
• Desensitization refers to a reduced response to an agonist drug due to over activation of a receptor (high doses, prolonged exposure to agonist).
• Drug Desensitization types?

  • Receptor mediated: Loss of function of receptors, Loss of number of receptors.
  • Non receptor mediated: Reduction in signaling or secondary messengers, Increase in metabolism of drug, Pathophysiological adaptation.
  • Dependence: The physical or psychological need for repeated drug dosing that is associated with adverse withdrawal effects in the absence of the drug.
• Downregulation refers to a reduction in the total number of receptors available to be stimulated due to prolonged receptor activation (e.g. by chronic treatment with a pharmacological agonist drug or prolonged inhibition of metabolism of a neurotransmitter). This reduction in receptors in turn will decrease the cell’s sensitivity to an agonist or drug. It occurs through endocytosis. Internalized receptors may either be degraded in the lysosomes or recycled back to the membrane surface later.
• Tolerance refers to a gradual decreased response to a drug, requiring a higher dose of drug to achieve the same initial response.
• Tolerance vs tachyphylaxis

  • Tolerance is different from tachyphylaxis because it develops over a long period of time, whereas, tachyphylaxis is an acute event.
  • tolerance can be overcome by increasing the dose, unlike tachyphylaxis.
• Tachyphylaxis is a rapid decrease in response to an agonist drug following repeated administration within a brief period; an acute form of desensitization.
• Loss of receptors in myasthenia gravis (pathophysiology)?

  • autoimmune disorder - produce antibodies destroy nicotinic acetylcholine receptors [nAChR] located in skeletal muscle.
  • These receptors help communicate signals resulting in muscle contraction.
  • Thus, Myasthenia Gravis causes muscle weakness, droopy eyes and even difficulty in swallowing.
  • treated with immunosuppressants to decrease the production of antibodies that destroy nAChRs and with acetylcholine esterase inhibitors [AChEIs] that prevent the breakdown of acetylcholine, a nAChR agonist, to increase its level in the synapse.