- Email: [email protected]
Drugs affecting the autonomic nervous system
PHARMACOLOGY
adoline is a peripherally acting κ opioid that has been shown to be antinociceptive in visceral models of pain. Asimadoline is an effective anti-arthritic drug, attenuating the joint damage and pain associated with adjuvant-induced arthritis in the rat and it is now on clinical trial for the treatment of osteoarthritis. Fedotozine is another agonist that has been used clinically, with some success, in irritable bowel syndrome and functional dyspepsia. However, there is some evidence that these beneficial effects are not always mediated via the k receptor. Fedotozine does not appear to have the diuretic action seen with other κ agonists. The original ligands for the δ receptor were the enkephalins. Highly selective ligands were developed based on the enkephalin peptide structure, but no commercially useful drug appeared. Nonpeptide δ agonists have been synthesized and show promise in animal studies but await trials in man. TAN-67 has been reported to mediate both spinal and supraspinal antinociceptive activity via the δ1 subgroup of opioid receptors. δ agonists, like the κ opioid agonists mentioned above, may have clinical applications not associated with classical analgesic activity. TAN-67 reduces infarct size and is cardioprotective in a rat model of coronary artery occlusion and re-perfusion In summary, while selective agonists at non-µ subtypes of opioid receptors exert analgesic properties, their clinical use may be limited to specific pathologies where pain relief is just one component of their beneficial action.
Drugs affecting the autonomic nervous system Barbara J Pleuvry
The autonomic nervous system has parasympathetic and sympathetic branches (Figure 1) and most pharmacological discussions concentrate on the efferent outflows of these two systems. The autonomic efferent pathway has two neurons that synapse at ganglia. In the case of the sympathetic nervous system, these ganglia lie close to the spinal cord in the paravertebral chain and the postganglionic fibre is long. The ganglia of the parasympathetic nervous system lie on, or close to, their effector organs, such that the postganglionic neuron is short.
Cholinergic neurotransmission in the autonomic nervous system Acetylcholine, interacting with nicotinic receptors, is the neurotransmitter at all autonomic ganglia. Drugs that stimulate or block these receptors do not differentiate between the sympathetic and parasympathetic ganglia. Nicotinic receptors are also found at the motor end plate of skeletal muscle. The molecular characteristics of the two receptors are different such that some nicotinic agonists and antagonists can have selectivity for the autonomic ganglia over the neuromuscular junction.
Pain and opioid sensitivity The standard method of postoperative pain control is the parenteral administration of opioids. Patient-controlled analgesia (PCA) is widely used to tailor opioid administration to an individual patient by titrating to an effective drug concentration and maintaining analgesia at that level. However, the ideal opioid for PCA, which has a fast onset of action, high efficacy, moderate duration of action and few side-effects, does not exist. Morphine is the standard opioid against which others are judged and there is often little credible evidence that other drugs have significant advantages. In severe pain, partial agonists may be ineffective if the ceiling to their effect occurs at low doses. The parenteral use of opioids is still a popular method of providing analgesia in obstetrics though it is associated with various side-effects on the fetus, including low Apgar scores and neurobehavioural deficits. Avoiding additional opioids after the first stage of labour can reduce these effects, but this may lead to inadequate pain relief. Spinal opioids are ineffective in labour. In chronic pain syndromes, neuropathic pain is often opioid insensitive. Figure 5 lists alternative routes that may be used to administer opioid drugs. u
Trimetaphan camsilate A number of fairly selective ganglion blockers have been developed, but only trimetaphan still has significant use in anaesthesia. Trimetaphan is used to induce controlled hypotension in surgery. Its mechanism of action involves ganglion blockade inhibiting the sympathetic tone maintaining blood pressure, release of histamine to cause peripheral vasodilation and a direct vasodilator effect. The principal advantage of trimetaphan over other ganglion-blocking agents is that it is short-acting and can be infused to give fine control of blood pressure. The effects of ganglion blockade on other effector systems depend on the dominant autonomic tone. In a fit young adult, sympathetic tone is dominant in the blood vessels and sweat glands while parasympathetic tone predominates at other sites.
FURTHER READING Bates J J, Foss J F, Murphy D B. Are peripheral opioid antagonists the solution to opioid side effects? Anesth Analg 2004; 98: 116–22. Calo G, Rizzi A, Bigoni R et al. Pharmacological profile of nociceptin/ orphanin FQ receptors. Clin Exp Pharmacol Physiol 2002; 29: 223–8. McCrimmon D R, Alheid G F. On the opiate trail of respiratory depression. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1274–5. Stein C, Machelska H, Schäfer M. Peripheral analgesic and antiinflammatory effects of opioids. Z Rheumatol 2001: 60: 416–24. Tseng L F. Evidence for ε-opioid receptor-mediated β-endorphin-induced analgesia. Trends Pharmacol Sci 2001; 22: 623–30.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
Barbara J Pleuvry is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK. She is a pharmacist by first degree but has been involved in teaching pharmacology to postgraduates and undergraduates for over 30 years. Her research interests include pain, analgesia and anticonvulsant drugs.
34
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Characteristics of the parasympathetic and sympathetic branches of the autonomic nervous system Brain
Parasympathetic ganglia
Parasympathetic medullary outflow
Acetylcholine Nicotinic receptor (ligand-gated ion channel)
Heart Paravertebral (sympathetic) ganglia
Heart Sweat glands
Sympathetic outflow
Spinal cord
Noradrenaline (norepinephrine)
Examples of effector organs
Muscarinic receptor (G-protein coupled)
Adrenal medulla Paravertebral (sympathetic) ganglia
Blood vessels
α-adrenoceptor (G-protein coupled)
Bladder Parasympathetic sacral outflow
β-adrenoceptor (G-protein coupled)
Parasympathetic ganglia
1
Anticholinesterase agents Acetylcholine interacts with G-protein-coupled muscarinic receptors on parasympathetic effector systems and some sympathetic effector systems (e.g. the sweat glands). There are five subtypes of muscarinic receptor (M1–M5). The physiological role of these receptors is uncertain and they will be discussed only when selective agonists or antagonists have a clinical efficacy. Pirenzepine, for example, is an antagonist with selectivity for M1 receptors and is used to inhibit gastric secretions in the treatment or prevention of gastric ulcers. Agonists at muscarinic receptors have limited use in anaesthesia, but muscarinic antagonists have been used in premedication (see Anaesthesia and Intensive Care Medicine 5:8: 250), during surgery to reverse bradycardia, and in conjunction with neostigmine during reversal of neuromuscular blockade. The action of acetylcholine is terminated when it is metabolized to choline and acetate by acetylcholinesterase (Figure 2). Acetylcholinesterase has two distinct active sites, an anionic site that attracts cationic groups and an esteratic site that produces catalytic hydrolysis of susceptible esters. In the case of acetylcholine, acetate is removed from the molecule and temporarily transferred to a serine-OH group present on the enzyme. Choline is freed and the serine acetyl group is rapidly hydrolysed. Neostigmine is an inhibitor of acetylcholinesterase that binds to both the anionic and esteratic sites on the acetylcholinesterase molecule. Instead of an acetyl group, neostigmine has a carbamyl group (Figure 2) that is transferred to the serine residues but it only slowly hydrolyses from the enzyme, resulting in a relatively long inhibition of the enzyme. Edrophonium is a very short-acting anticholinesterase agent. It is a quaternary ammonium compound that binds only to the anionic site of the enzyme and is thus readily reversible. Its main clinical use is for the diagnosis of myasthenia gravis, but it has been used in anaesthesia as an alternative to neostigmine. When reversing neuromuscular blockade, anticholinesterase agents preserve the action of acetylcholine at the neuromuscular junction thus antagonizing the competitive blockade of nicotinic receptors by neuromuscular blocking agents. Acetylcholine is also preserved at muscarinic sites and this could lead to excessive activation of the receptors with resultant bradycardia. This is prevented by the co-administration of a muscarinic antagonist, usually atropine.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
Glycopyrrolate is sometimes used as an alternative to atropine because it is devoid of CNS effects and its placental transfer is minimal. It also has less effect on heart rate and pupil size.
Adrenergic neurotransmission in the autonomic nervous system Many drugs included under this heading are used to modulate myocardial function, vascular resistance and blood pressure and some aspects of their pharmacology are discussed in Anaesthesia and Intensive Care Medicine 5:2. The neurotransmitter used at most sympathetic effector organs is noradrenaline. The exceptions are acetylcholine, released at the sweat glands and possibly in skeletal muscle blood vessels, and adrenaline, released from the adrenal medulla. The major subdivisions of the α- and β-adrenoceptors and the principal pharmacological effects of their stimulation relevant to the autonomic nervous system are given in Figure 3.
Metabolism of acetylcholine O C OCH2CH2N+(CH3)3
x
CH3 Acetylcholine
Acetylcholinesterase cho H3C N
CH3COOAcetate
C
H3C O
CH3 N+
CH3
CH3 Neostigmine
+
OH CH2CH2N+(CH3)3 Choline
2
35
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Adrenoceptors Receptor α1
α2
β1
β2
β3
1
Principal responses to stimulation Contraction of smooth muscle in blood vessels, bronchi, gastrointestinal and bladder sphincters, uterus and radial muscle of iris Relaxation of smooth muscle in gastrointestinal tract Contraction of smooth muscle in blood vessels Decreased release of noradrenaline and acetylcholine Increase in heart rate, force of cardiac contraction Increased release of noradrenaline Relaxation of smooth muscle in blood vessels, bronchi, gastrointestinal tract, bladder and radial muscles of iris Tremor and increased skeletal muscle mass Glycogenolysis Thermogenesis Lipolysis
Selective agonist Phenylephrine
Selective antagonist Prazosin
Clonidine Dexmedetomidine
Yohimbine1
Dobutamine Xamoterol
Atenolol
Salbutamol
Butoxamine1
Not clinically available.
3
Sympathomimetic drugs Both norepinephrine and epinephrine act on all adrenoceptors though norepinephrine has more activity on α-receptors than does epinephrine. Intravenous administration of norepinephrine results in a decrease in heart rate caused by the reflex response of the baroreceptors to the increase in blood pressure that occurs as a consequence of intense α-receptor-induced vasoconstriction increasing peripheral resistance. Epinephrine, in contrast, causes vasoconstriction, some vasodilatation in skeletal muscle blood vessels and a moderate increase in heart rate. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) break down norepinephrine and epinephrine such that their plasma elimination half-life is a matter of minutes. More prolonged α-adrenoceptor stimulation can be achieved with a nonselective α-adrenoceptor agonist (e.g. methoxamine). Clonidine is usually used in anaesthesia for its sedative, general anaesthetic sparing and analgesic effects that are mediated by α2-adrenoceptor activation in the CNS. Clonidine has been used as a peripherally acting antihypertensive agent by reducing adrenaline release via an action on presynaptic receptors, but it is usually considered to be too long-acting to be used for this purpose in anaesthesia. Hypotensive complications in obstetric anaesthesia may be treated with ephedrine. It has direct effects on α- and β-adrenoceptors and releases noradrenaline from sympathetic nerve endings. This combination of effects is less likely (than α-adrenoceptor agonists) to reduce placental perfusion and thus preserves fetal oxygenation. However, ephedrine crosses the placental barrier and the blood–brain barrier in the mother, where it has an amphetamine-like effect. Dopamine also combines α- and β-adrenoceptor stimulation. In addition, it causes renal and mesenteric vasodilatation by an
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
action on dopamine (D1) receptors in the vasculature. Its main use in anaesthesia is as an inotrope in low cardiac output states. Similarly, dobutamine (a β1-selective agonist) and dopexamine (a β2- and D1-receptor agonist) are mainly used as inotropic agents. Drugs that block adrenoceptors Prazosin (a selective α1-adrenoceptor antagonist), atenolol and esmolol (a selective β1-adrenoceptor antagonists), propranolol, oxprenolol and sotolol (non-selective β-adrenoceptor antagonists, which act on both β1 and β2 receptors), are mainly used for the treatment of chronic hypertension. In anaesthesia, β-adrenoceptor antagonists are used to treat cardiac arrhythmias associated with dental extractions, cardiac or vascular procedures, thyroidectomy and the removal of phaeochromocytoma. Esmolol is rapidly metabolized by blood esterases and may be given by infusion. The antidysrhythmic actions of some agents are related to their additional properties, such as sodium channel blockade for propranolol and oxprenolol (a partial agonist), or potassium channel blockade for sotolol. Typical adverse effects of excessive dose are bradyarrhythmias and hypotension. u
FURTHER READING Rang H P, Dale M M, Ritter J M, Moore P K. Cholinergic transmission. In: Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003, 136–60. Rang H P, Dale M M, Ritter J M, Moore P K. Noradrenergic transmission. In: Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003, 161–83.
36
© 2005 The Medicine Publishing Company Ltd
adoline is a peripherally acting κ opioid that has been shown to be antinociceptive in visceral models of pain. Asimadoline is an effective anti-arthritic drug, attenuating the joint damage and pain associated with adjuvant-induced arthritis in the rat and it is now on clinical trial for the treatment of osteoarthritis. Fedotozine is another agonist that has been used clinically, with some success, in irritable bowel syndrome and functional dyspepsia. However, there is some evidence that these beneficial effects are not always mediated via the k receptor. Fedotozine does not appear to have the diuretic action seen with other κ agonists. The original ligands for the δ receptor were the enkephalins. Highly selective ligands were developed based on the enkephalin peptide structure, but no commercially useful drug appeared. Nonpeptide δ agonists have been synthesized and show promise in animal studies but await trials in man. TAN-67 has been reported to mediate both spinal and supraspinal antinociceptive activity via the δ1 subgroup of opioid receptors. δ agonists, like the κ opioid agonists mentioned above, may have clinical applications not associated with classical analgesic activity. TAN-67 reduces infarct size and is cardioprotective in a rat model of coronary artery occlusion and re-perfusion In summary, while selective agonists at non-µ subtypes of opioid receptors exert analgesic properties, their clinical use may be limited to specific pathologies where pain relief is just one component of their beneficial action.
Drugs affecting the autonomic nervous system Barbara J Pleuvry
The autonomic nervous system has parasympathetic and sympathetic branches (Figure 1) and most pharmacological discussions concentrate on the efferent outflows of these two systems. The autonomic efferent pathway has two neurons that synapse at ganglia. In the case of the sympathetic nervous system, these ganglia lie close to the spinal cord in the paravertebral chain and the postganglionic fibre is long. The ganglia of the parasympathetic nervous system lie on, or close to, their effector organs, such that the postganglionic neuron is short.
Cholinergic neurotransmission in the autonomic nervous system Acetylcholine, interacting with nicotinic receptors, is the neurotransmitter at all autonomic ganglia. Drugs that stimulate or block these receptors do not differentiate between the sympathetic and parasympathetic ganglia. Nicotinic receptors are also found at the motor end plate of skeletal muscle. The molecular characteristics of the two receptors are different such that some nicotinic agonists and antagonists can have selectivity for the autonomic ganglia over the neuromuscular junction.
Pain and opioid sensitivity The standard method of postoperative pain control is the parenteral administration of opioids. Patient-controlled analgesia (PCA) is widely used to tailor opioid administration to an individual patient by titrating to an effective drug concentration and maintaining analgesia at that level. However, the ideal opioid for PCA, which has a fast onset of action, high efficacy, moderate duration of action and few side-effects, does not exist. Morphine is the standard opioid against which others are judged and there is often little credible evidence that other drugs have significant advantages. In severe pain, partial agonists may be ineffective if the ceiling to their effect occurs at low doses. The parenteral use of opioids is still a popular method of providing analgesia in obstetrics though it is associated with various side-effects on the fetus, including low Apgar scores and neurobehavioural deficits. Avoiding additional opioids after the first stage of labour can reduce these effects, but this may lead to inadequate pain relief. Spinal opioids are ineffective in labour. In chronic pain syndromes, neuropathic pain is often opioid insensitive. Figure 5 lists alternative routes that may be used to administer opioid drugs. u
Trimetaphan camsilate A number of fairly selective ganglion blockers have been developed, but only trimetaphan still has significant use in anaesthesia. Trimetaphan is used to induce controlled hypotension in surgery. Its mechanism of action involves ganglion blockade inhibiting the sympathetic tone maintaining blood pressure, release of histamine to cause peripheral vasodilation and a direct vasodilator effect. The principal advantage of trimetaphan over other ganglion-blocking agents is that it is short-acting and can be infused to give fine control of blood pressure. The effects of ganglion blockade on other effector systems depend on the dominant autonomic tone. In a fit young adult, sympathetic tone is dominant in the blood vessels and sweat glands while parasympathetic tone predominates at other sites.
FURTHER READING Bates J J, Foss J F, Murphy D B. Are peripheral opioid antagonists the solution to opioid side effects? Anesth Analg 2004; 98: 116–22. Calo G, Rizzi A, Bigoni R et al. Pharmacological profile of nociceptin/ orphanin FQ receptors. Clin Exp Pharmacol Physiol 2002; 29: 223–8. McCrimmon D R, Alheid G F. On the opiate trail of respiratory depression. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1274–5. Stein C, Machelska H, Schäfer M. Peripheral analgesic and antiinflammatory effects of opioids. Z Rheumatol 2001: 60: 416–24. Tseng L F. Evidence for ε-opioid receptor-mediated β-endorphin-induced analgesia. Trends Pharmacol Sci 2001; 22: 623–30.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
Barbara J Pleuvry is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK. She is a pharmacist by first degree but has been involved in teaching pharmacology to postgraduates and undergraduates for over 30 years. Her research interests include pain, analgesia and anticonvulsant drugs.
34
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Characteristics of the parasympathetic and sympathetic branches of the autonomic nervous system Brain
Parasympathetic ganglia
Parasympathetic medullary outflow
Acetylcholine Nicotinic receptor (ligand-gated ion channel)
Heart Paravertebral (sympathetic) ganglia
Heart Sweat glands
Sympathetic outflow
Spinal cord
Noradrenaline (norepinephrine)
Examples of effector organs
Muscarinic receptor (G-protein coupled)
Adrenal medulla Paravertebral (sympathetic) ganglia
Blood vessels
α-adrenoceptor (G-protein coupled)
Bladder Parasympathetic sacral outflow
β-adrenoceptor (G-protein coupled)
Parasympathetic ganglia
1
Anticholinesterase agents Acetylcholine interacts with G-protein-coupled muscarinic receptors on parasympathetic effector systems and some sympathetic effector systems (e.g. the sweat glands). There are five subtypes of muscarinic receptor (M1–M5). The physiological role of these receptors is uncertain and they will be discussed only when selective agonists or antagonists have a clinical efficacy. Pirenzepine, for example, is an antagonist with selectivity for M1 receptors and is used to inhibit gastric secretions in the treatment or prevention of gastric ulcers. Agonists at muscarinic receptors have limited use in anaesthesia, but muscarinic antagonists have been used in premedication (see Anaesthesia and Intensive Care Medicine 5:8: 250), during surgery to reverse bradycardia, and in conjunction with neostigmine during reversal of neuromuscular blockade. The action of acetylcholine is terminated when it is metabolized to choline and acetate by acetylcholinesterase (Figure 2). Acetylcholinesterase has two distinct active sites, an anionic site that attracts cationic groups and an esteratic site that produces catalytic hydrolysis of susceptible esters. In the case of acetylcholine, acetate is removed from the molecule and temporarily transferred to a serine-OH group present on the enzyme. Choline is freed and the serine acetyl group is rapidly hydrolysed. Neostigmine is an inhibitor of acetylcholinesterase that binds to both the anionic and esteratic sites on the acetylcholinesterase molecule. Instead of an acetyl group, neostigmine has a carbamyl group (Figure 2) that is transferred to the serine residues but it only slowly hydrolyses from the enzyme, resulting in a relatively long inhibition of the enzyme. Edrophonium is a very short-acting anticholinesterase agent. It is a quaternary ammonium compound that binds only to the anionic site of the enzyme and is thus readily reversible. Its main clinical use is for the diagnosis of myasthenia gravis, but it has been used in anaesthesia as an alternative to neostigmine. When reversing neuromuscular blockade, anticholinesterase agents preserve the action of acetylcholine at the neuromuscular junction thus antagonizing the competitive blockade of nicotinic receptors by neuromuscular blocking agents. Acetylcholine is also preserved at muscarinic sites and this could lead to excessive activation of the receptors with resultant bradycardia. This is prevented by the co-administration of a muscarinic antagonist, usually atropine.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
Glycopyrrolate is sometimes used as an alternative to atropine because it is devoid of CNS effects and its placental transfer is minimal. It also has less effect on heart rate and pupil size.
Adrenergic neurotransmission in the autonomic nervous system Many drugs included under this heading are used to modulate myocardial function, vascular resistance and blood pressure and some aspects of their pharmacology are discussed in Anaesthesia and Intensive Care Medicine 5:2. The neurotransmitter used at most sympathetic effector organs is noradrenaline. The exceptions are acetylcholine, released at the sweat glands and possibly in skeletal muscle blood vessels, and adrenaline, released from the adrenal medulla. The major subdivisions of the α- and β-adrenoceptors and the principal pharmacological effects of their stimulation relevant to the autonomic nervous system are given in Figure 3.
Metabolism of acetylcholine O C OCH2CH2N+(CH3)3
x
CH3 Acetylcholine
Acetylcholinesterase cho H3C N
CH3COOAcetate
C
H3C O
CH3 N+
CH3
CH3 Neostigmine
+
OH CH2CH2N+(CH3)3 Choline
2
35
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Adrenoceptors Receptor α1
α2
β1
β2
β3
1
Principal responses to stimulation Contraction of smooth muscle in blood vessels, bronchi, gastrointestinal and bladder sphincters, uterus and radial muscle of iris Relaxation of smooth muscle in gastrointestinal tract Contraction of smooth muscle in blood vessels Decreased release of noradrenaline and acetylcholine Increase in heart rate, force of cardiac contraction Increased release of noradrenaline Relaxation of smooth muscle in blood vessels, bronchi, gastrointestinal tract, bladder and radial muscles of iris Tremor and increased skeletal muscle mass Glycogenolysis Thermogenesis Lipolysis
Selective agonist Phenylephrine
Selective antagonist Prazosin
Clonidine Dexmedetomidine
Yohimbine1
Dobutamine Xamoterol
Atenolol
Salbutamol
Butoxamine1
Not clinically available.
3
Sympathomimetic drugs Both norepinephrine and epinephrine act on all adrenoceptors though norepinephrine has more activity on α-receptors than does epinephrine. Intravenous administration of norepinephrine results in a decrease in heart rate caused by the reflex response of the baroreceptors to the increase in blood pressure that occurs as a consequence of intense α-receptor-induced vasoconstriction increasing peripheral resistance. Epinephrine, in contrast, causes vasoconstriction, some vasodilatation in skeletal muscle blood vessels and a moderate increase in heart rate. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) break down norepinephrine and epinephrine such that their plasma elimination half-life is a matter of minutes. More prolonged α-adrenoceptor stimulation can be achieved with a nonselective α-adrenoceptor agonist (e.g. methoxamine). Clonidine is usually used in anaesthesia for its sedative, general anaesthetic sparing and analgesic effects that are mediated by α2-adrenoceptor activation in the CNS. Clonidine has been used as a peripherally acting antihypertensive agent by reducing adrenaline release via an action on presynaptic receptors, but it is usually considered to be too long-acting to be used for this purpose in anaesthesia. Hypotensive complications in obstetric anaesthesia may be treated with ephedrine. It has direct effects on α- and β-adrenoceptors and releases noradrenaline from sympathetic nerve endings. This combination of effects is less likely (than α-adrenoceptor agonists) to reduce placental perfusion and thus preserves fetal oxygenation. However, ephedrine crosses the placental barrier and the blood–brain barrier in the mother, where it has an amphetamine-like effect. Dopamine also combines α- and β-adrenoceptor stimulation. In addition, it causes renal and mesenteric vasodilatation by an
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:1
action on dopamine (D1) receptors in the vasculature. Its main use in anaesthesia is as an inotrope in low cardiac output states. Similarly, dobutamine (a β1-selective agonist) and dopexamine (a β2- and D1-receptor agonist) are mainly used as inotropic agents. Drugs that block adrenoceptors Prazosin (a selective α1-adrenoceptor antagonist), atenolol and esmolol (a selective β1-adrenoceptor antagonists), propranolol, oxprenolol and sotolol (non-selective β-adrenoceptor antagonists, which act on both β1 and β2 receptors), are mainly used for the treatment of chronic hypertension. In anaesthesia, β-adrenoceptor antagonists are used to treat cardiac arrhythmias associated with dental extractions, cardiac or vascular procedures, thyroidectomy and the removal of phaeochromocytoma. Esmolol is rapidly metabolized by blood esterases and may be given by infusion. The antidysrhythmic actions of some agents are related to their additional properties, such as sodium channel blockade for propranolol and oxprenolol (a partial agonist), or potassium channel blockade for sotolol. Typical adverse effects of excessive dose are bradyarrhythmias and hypotension. u
FURTHER READING Rang H P, Dale M M, Ritter J M, Moore P K. Cholinergic transmission. In: Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003, 136–60. Rang H P, Dale M M, Ritter J M, Moore P K. Noradrenergic transmission. In: Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003, 161–83.
36
© 2005 The Medicine Publishing Company Ltd