Medical Pharmacology Chapter 4: Autonomic (ANS) Pharmacology: Introduction
Adrenergic Neurotransmission: Introduction to the Neurotransmitters
Norepinephrine: transmitter released at most postganglionic sympathetic terminals
Dopamine: major CNS neurotransmitter of mammalian extrapyramidal system and some mesocortical and mesolimbic neurononal pathways.
Epinephrine: most important hormone of the adrenal medulla
Catecholamine Synthesis, Storage, and Release
Aromatic L-amino acid decarboxylase (DOPA decarboxylase)
Dopa leads to dopamine
Methyldopa leads to a-methyldopamine (converted by dopamine β hydroxylase to the "false transmitter" α-norepinephrine)
5-hydroxy-L-tryptophanleads to5-hydroxytryptamine (5-HT)
Tyrosine leads to DOPA
Rate limiting step in pathway
Ttyrosine hydroxylase is a substrate for cAMP-dependent and Ca2+ - calmodulin-sensitive protein kinase and protein kinase C
Increased hydroxylase activity is associated with the phosphorylated enzyme
In adrenergically innervated tissue: norepinephrine is localized in post-ganglionic nerve terminals
Large dense core vesicles (corresponding to chromaffin granules)
Small dense core vesicles (containing norepinephrine, ATP, and membrane-bound dopamine β-hydroxylase
In the adrenal medulla, catecholamines are localized in chromaffin granules.
The most abundant catecholamine in the adrenal medulla is epinephrine.
The adrenal medulla has two cells types containing catecholamines:
One type contains mainly norepinephrine
The second type contains mainly epinephrine.
Epinephrine-containing cells express cytoplasmic phenylethanolamine-N-methyl transferase, allowing conversion of norepinephrine to epinephrine.
Synthesized in granules
Diffuses out, is methylated in the cytoplasm to epinephrine
Then reenters the chromaffin granules.
About half of dopamine is formed in sympathetic neuronal cytoplasm is actively translocated into dopamine β-hydroxylase-containing vesicles, where the final step, conversion to norepinephrine occurs.
The remaining dopamine is converted to homovanillic acid.
Regulation of Adrenal Medullary Catecholamine Levels
An important factor controlling the rate of epinephrine synthesis and adrenal medullary epinephrine concentration is glucocorticoid concentration.
Are secreted by the adrenal cortex
Are carried by an intra-adrenal portal vascular system to the adrenal medullary chromaffin cells
Induce synthesis of phenylethanolamine-N-methytransferase.
Also increase levels of tyrosine hydroxylase and dopamine β-hydroxylase.
Stress leads to increased corticotropin leads to increased cortisol, increased epinephrine
Following release from adrenergic nerve endings, termination of norepinephrine effect is mainly due to reuptake into presynaptic terminals.
In tissues with wide synaptic gaps and in blood vessels, the effect of released norepinephrine is ended by:
Diffusion away from receptors
Neuronal norepinephrine reuptake requires two systems:
A transport system that translocates norepinephrine from extraneuronal spaces into cytoplasm.
A transport system that translocates norepinephrine from the cytoplasm into vesicles.
Translocation of norepinephrine from extraneuronal spaces (uptake I) into the cytoplasm is blocked by:
Tricyclic antidepressants (e.g. imipramine (Tofranil))
Imipramine (Tofranil) : Tricyclic Antidepressant
Inhibits norepinephrine and serotonin reuptake
Orthostatic hypotension due to α-receptor blockade
Endogenous depression (an serotonin-specific reuptake inhibitor (SSRI) or other second generation agent is likely to be used first)
Occasionally, reactive depression
Treatment of enuresis in children older than six.
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 616-619
Mechamisms of Indirect Acting Sympathomimetics
An indirect acting sympathomimetic acts mainly by promoting norepinephrine release from nerve terminals.
Mechanism: These amines, all substates for uptake I, act by:
competing with noradrenergic vesicular transport systems, thus making norepinephine more available for release.
Indirect-acting agents, such as tyramine, produce tachyphylaxis in which repetitive doses of tyramine results in a progressively diminishing response.
Tachyphylaxis may result from depletion of a small pool of vesicular norepinphrine residing near the presynaptic membrane.
Uptake II is an extraneuronal (glia, heart, liver, etc )amine translocator that exhibits low affinity for norepinephrine and higher affinities for epinephrine and isoproterenol. This system is of limited physiological significance, unless Uptake I is blocked.
Besides reuptake and diffusion away from receptor sites, catecholamine action can end due to metabolic transformation.
Two primary degradative enzymes:
Monoamine Oxidase (MAO)
Catechol-O-Methyl Transferase (COMT)
Inhibitors of MAO, such as pargyline, phenelzine (Nardil), and tranylcypromine (Parnate) increase norepinephrine, dopamine, and serotonin (5-HT) brain concentrations.
These concentration increases may be responsible for antidepressant action of MAO inhibitors.
Monoamine Oxidase Inhibitor: Phenelzine [Nardil]
Hydrazine MAO inhibitor with amphetamine-like activity
Termination of drug action requires new MAO enzyme synthesis
May cause Hypertensive crisis
Rreatment of endogenous depression
Management of depressive phase of bipolar disorder
Treatment of severe reactive depression not responsive to other drugs.
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 904-905
Catecholamine Release (Adrenal medulla)
Release steps: Chromaffin Granule Adrenal medulla
Preganglion fiber releases Ach →nicotinic receptor activation→depolarization→Ca2+ entry →exocytosis of granular content
Ca2+ influx is important in excitation (depolarization)--release coupling
Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.112-137
Order of agonist potency
Isoproterenol > epinephrine > norepinephrine
β receptors are divided into two major categories: β1 and β2.
β1 receptors → myocardium.
β2 receptors → smooth muscle and most other sites.
The subdivision of beta receptors followed from the observation that in the heart norepinephrine and epinephrine were equipotent, whereas epinephrine was many fold (10 - 50) more potent at smooth muscle.
A β3 receptor has been found that is strongly activated by norepinephrine compared to epinephrine and may explain "atypical" pharmacological properties of adipose tissue.
The β3 -receptor is not blocked by propranolol, classified as a non selective beta-receptor blocker.
The β3 -receptor is not blocked by propranolol, classified as a non selective beta-receptor blocker.
Activation of β1, β2 and β3 receptors increases adenylyl cyclase activity (Gs mediated) resulting in a rise of intracellular cAMP.
Cardiac inotropic effects result from increases in Ca2+ concentration, due to:
phosphorylation of L-type Ca2+ channels
phosphorylation of sarcolemmal Ca2+ pumps
direct action Gs action on the L-type channel
Effects on the liver lead to activation of glycogen phosphorylation
β2 receptor activation mediates relaxation of vascular smooth muscle
β2 receptor activation mediates relaxation of G.I. smooth muscle. α2 adrenergic receptor activation acts presynaptically to reduce Ach release and promote G.I. smooth muscle relaxation.
The α2 receptor effect is the more important.
Order of agonist potency
epinephrine > norepinephrine >> isoproterenol
Multiple α receptor subtypes have been identified.
Multiple forms were suggested when, after administration of an α-receptor antagonist, repetitive nerve stimulation resulted in increasing amount of norepinephrine release. This findings suggested a presynaptic α-receptor binding site.
Post-synaptic receptors→ α1 .
Pre-synaptic receptors→ α2 .
α2 receptors are also present post-synaptically. This site is involved in the action of some centrally-acting antihypertensive agents, e.g. clonidine.
Some drugs, such as clonidine are more active at α2 receptors.
Clonidine acts in the brain at post-synaptic α2 receptors, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.
Clonidine reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance. Reduction in stoke volume occurs due to increased venous pooling (decreased preload).
Clonidine does not interfere with cardiovascular responses to exercise.
Renal blood flow and function is maintained during clonidine treatment.
Clonidine has minimal or no effect on plasma lipids.
Dry Mouth (xerostomia)
Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors)
Bradycardia (in patients with SA nodal abnormality)
Some drugs such as methoxamine (Vasoxyl) or phenylephrine (Neo-Synephrine) are more active at α1 receptors.
Multiple forms of both α1 and α2 receptors have been identified.
D1 receptor activation results in stimulation of adenylyl cyclase activity.
Smooth muscle relaxation (e.g. renal vasodilation) would result from increases in cAMP caused by activation of D1 receptors
Increased cAMP levels may facilitate inactivation of myosin light chain kinase, MLK (activated by calcium-calmodulin complexes which means that increased Ca2+ promotes MLK activation).
Note that only phosphylated myosin can bind to actin and that phosphorylation state is controlled by the enzyme myosin light chain kinase.
D2 receptor activation inhibits cAMP production (inhibits adenylyl cyclase activity), increases K+ conductance and decreases calcium influx.
Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
Regulation of catecholamine responsiveness occurs at several levels:
Cyclic nucleotide phosphodiesterase
Stimulation of β-adrenergic receptors rapidly causes receptor phosphorylation and decreased responsiveness. The phosphorylated receptor exhibits:
Decreased coupling to Gs and
Decreased stimulation of adenylyl cyclase.
Other Autonomic Neurotransmitters/Cotransmitters
ATP and catecholamines are found together in neuronal and adrenal medullary storage granules. ATP is released along with transmitters and, in certain cases, has an important role in synaptic transmission.
Vasoactive Intestinal Peptide (VIP)
Vasoactive intestinal peptide (VIP) is found in association with ACh in autonomic parasympathetic fibers innervating blood vessels and exocrine glands and cholinergic sympathetic fibers innervating sweat glands.
VIP may be involved in salivation, tracheal and the GI tract responsiveness to parasympathetic input.
The neuropeptide Y family includes NPY, pancreatic polypeptide, and peptide YY.
NPY in the periphery is associated with sympathetic fibers and assists in maintaining vascular tone.
NPY is a potent, long-lasting vasoconstrictor, especially of small vessels
Purines such as ATP and adenosine may be responsible for apparent non-cholinergic, non-adrenergic autonomic neurotransmission.
Blood vessel endothelium is required for ACh-mediated smooth muscle relaxation.
The endothelial cell layer modulates vessel responsiveness to autonomic and hormonal influences.
Endothelial cell elaborate endothelium-derived relaxing factor (EDRF, nitric oxide) and a contracting factor.
Pharmacological actions of serotonin, histamine, bradykinin, purines, thrombin are mediated to some degree by stimulation of EDRF release.
Endothelial-released nitric oxide diffuses into vascular smooth muscle and activates guanylyl cyclase which increases cGMP.
Clinically, hypotension associated with endotoxemia may be mediated partially by increased release of nitric oxide. A similar mechanism is proposed for hypotension induced by cytokines.
Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.112-137.Hoffman, B. B. Adrenoceptor-Activating & Other Sympathomimetic Drugs: Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p.118-122