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310 Cards in this Set
- Front
- Back
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What is the role of the autonomic nervous system?
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In voluntary regulation of cardiovascular, gastrointestinal, and thermal homeostasis of the human body
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How does this relate to anesthesiology?
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The success of anesthetic management often depends on the maintenance of homeostasis in a variety of changing situations, so anesthesiology has been called the practice of ANS medicine
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What is most practical preoperative test for evaluation of ANS functions?
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The determination of orthostasis, with ANS dysfunction suggested by a decrease in systolic blood pressure of more than 30 mmHg and the absence of an increase in heart rate from assuming upright posture
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Drugs to be covered during this chapter
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Catecholamines, sympathomimetic's, antihypertensives, beta adrenergic agonists, beta – adrenergic antagonists, anticholinergics, and anti-cholinesterases
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What makeup the central ANS?
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The hypothalamus, medulla, and pons
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Which site is the highest level of ANS integration?
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The cerebral cortex
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What is the principal site for ANS organization and body responses to stress, systematic blood pressure control, and temperature regulation?
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The hypothalamic nuclei
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Role of the medulla and pons in the ANS
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They are vital centers for hemodynamic and ventilatory control, integrating and maintaining the automaticity of ventilation
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What is the peripheral ANS divided into?
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The sympathetic nervous system, or the thoracolumbar nervous system, and the parasympathetic nervous system, or craniosacral nervous system
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what is released by preganglionic and postganglionic fibers of the parasympathetic nervous system?
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Acetylcholine
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What is released by postganglionic fibers of the sympathetic nervous system? And what is the exception?
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Norepinephrine, the exception are fibers to sweat glands which release acetylcholine
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Where do preganglionic fibers of the sympathetic and parasympathetic nervous systems originate?
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Preganglionic fibers of the sympathetic nervous system arise from cells in the thoracolumbar portions of the spinal cord, where is the cell bodies of the preganglionic fibers of the parasympathetic nervous system originate in the craniosacral region
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Makeup of the sympathetic and parasympathetic nervous systems
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First-order neurons of both systems originate within the central nervous system, and preganglionic fibers relay impulses to second order neurons known as the autonomic ganglia, which contain the cell bodies of the postganglionic fibers responsible for relaying information to effector organs
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What is the difference between preganglionic fibers and postganglionic fibers of the SNS and PNS?
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Preganglionic fibers are myelinated, i.e. rapid – conduction fibers, and postganglionic fibers are non-myelinated
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Distribution of postganglionic fibers of the SNS versus PNS
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Postganglionic fibers of the SNS are distributed throughout the body and are responsible for more generalized mass reflex response, where is the distribution of PNS is more limited with the PNS having its terminal ganglia near the organ innervated and is more discreet in discharge of impulses
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Where did the preganglionic fibers of the SNS originate?
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In the intermedia lateral column of thoracic, T-1 to T 12, and the first three lumbar segments, L1 to L3, of the spinal cord
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Makeup of the SNS
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Myelinated motor nerves leave the spinal cord as white communicating fibers and enter one of the paired chains of 22 sympathetic ganglia; the fibers originating from these ganglia synapse within the ganglion, synapse in the ganglion at other levels, and emerge as postganglionic fibers, or exit as preganglionic fibers to synapse in outlying unpaired ganglia such as celiac or mesenteric ganglia
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What is the exception to these rules?
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The adrenal gland, which receives preganglionic fibers directly
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What type of receptors to effector organs of the SNS have?
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Adrenergic receptors
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How are adrenergic receptors characterized?
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As alpha or beta, and dopamine receptors
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What neurotransmitter is released at the preganglionic and postganglionic fibers for both the SNS and PNS?
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Acetylcholine is released it preganglionic fibers of both the SNS and PNS, for SNS Oce ganglionic fibers norepinephrine or dopamine is a neurotransmitter
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What does norepinephrine do at the synapse?
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Stimulates alpha and beta adrenergic receptors
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What does dopamine do?
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Stimulate dopamine receptors present on the effector site
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Classes of receptors
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Multiple classes of alpha and dopamine receptors have been identified: alpha-1, alpha-2, D1 to D5
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Alpha-1 receptors
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Are mostly localized on the postsynaptic membranes of vascular and intestinal smooth muscle and endocrine glands, with a few present in the heart
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Alpha-2 receptors
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Are usually presynaptic, except in the CNS, and functioning and negative – feedback loop such that their activation inhibits subsequent release of neurotransmitter
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Beta-1 receptor effector organs
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Heart, fat cells
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Response of the heart to beta-1 stimulation
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Increased heart rate, increased contractility, and increased conduction velocity
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Beta-1 agonists
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Dobutamine, dopamine, isoproterenol
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What is unique about isoproterenol?
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Produces mixed the beta-1 and beta-2 effects
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Beta-1 antagonists
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Metoprolol, esmolol, propranolol, timolol, labetolol
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Which beta blockers produced mixed beta-1 and beta-2 effects?
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Propranolol, timolol, labetolol
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Response to beta-1 stimulation of fat cells
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Lipolysis
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Beta-2 receptor effector organs
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Blood vessels (especially skeletal and coronary arteries), bronchioles, uterus, kidneys, liver, pancreas
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Response of blood vessels to beta-2 stimulation
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Dilation
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Response of bronchioles to beta-2 stimulation
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Dilation
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Response of uterus to beta-2 stimulation
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Relaxation
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Response of kidneys to beta-2 stimulation
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Renin secretion
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Response of the liver to beta-2 stimulation
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Glycogenolysis and gluconeogenesis
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Response of the pancreas to beta-2 stimulation
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Insulin secretion
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Beta-2 agonists
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Albuterol, ritodrine
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Beta-2 antagonists
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Propranolol, timolol, labetolol (all have mixed beta-1 and beta-2 effects)
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Alpha-1 receptor effector organs
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Blood vessels, pancreas, intestine and bladder
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Response of blood vessels to alpha-1 stimulation
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Constriction
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Response of the pancreas to alpha-1 stimulation
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Inhibition of insulin secretion
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Response of the intestines and bladder to alpha-1 stimulation
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Relaxation and constriction of sphincters
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Alpha-1 agonists
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Phenylephrine
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Alpha-1 antagonists
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Prazosin, phentolamine, labetolol
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Which alpha-1 antagonist produces mixed alpha-1 and alpha-2 effects?
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Phentolamine
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Alpha-2 effector organs
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Postganglionic (presynaptic sympathetic nerve ending), central nervous system (postsynaptic), and platelets
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Response of postganglionic fibers to alpha-2 stimulation
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Inhibition of norepinephrine release
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Response of the central nervous system to alpha-2 stimulation
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Increasing potassium conductance?
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Response of platelets to alpha-2 stimulation
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Aggregation
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Alpha-2 agonists
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Clonidine, dexmedetomidine
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Alpha-2 antagonists
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Yohimbine, phentolamine
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Dopamine one receptor effector organs
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Blood vessels
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Response of blood vessels to dopamine one receptor stimulation
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Dilation
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D1 agonists
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fenoldopam
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D1 antagonists
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droperidol
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D2 effector organs
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Postganglionic (presynaptic) sympathetic nerve endings
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Response postganglionic sympathetic nerve endings to D2 stimulation
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Inhibition of norepinephrine release
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D2 agonists
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Dopamine
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D2 antagonists
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domperidone
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Muscarinic receptor effector organs
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Heart, bronchioles, salivary glands, intestine, bladder
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Response of the heart to muscarinic receptor stimulation
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Decreased heart rate, decreased contractility, decreased conduction velocity
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Response of bronchioles to muscarinic receptor stimulation
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Constriction
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Response of salivary glands to muscarinic receptor stimulation
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Stimulation of secretions
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Response of the intestines to muscarinic receptor stimulation
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Contraction, relaxation of sphincters, stimulation of secretions
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Responsible bladder to muscarinic receptor stimulation
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Contraction, relaxation of sphincters
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Muscarinic agonists
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Methacholine, carbachol
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Muscarinic receptor antagonists
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Atropine, scopolamine, glycopyrrolate
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Nicotinic receptor effector organs
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Neuromuscular junction, autonomic ganglia
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Response of the neuromuscular junction to nicotinic receptor stimulation
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Skeletal muscle contraction
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Response of the autonomic ganglia nicotinic receptor stimulation
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Sympathetic nervous system stimulation
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Nicotinic agonists
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Succinylcholine
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Nicotinic antagonists
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Non-depolarizing muscle relaxants
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How is the action of endogenously released catecholamines at the synaptic cleft terminated?
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By three mechanisms: uptake into the presynaptic terminals and storage and norepinephrine vesicles for reuse; extra neuronal uptake or reuptake, in which norepinephrine is metabolized by monoamine oxidase and catecholamine – O– methyltransferase to form vanillylmandelic acid; and diffusion
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How does termination of an endogenously released norepinephrine activity most exclusively occur?
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By uptake back in the storage vesicles
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What is the predominant pathway for inactivation of the effects produced by catecholamines administered exogenously?
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Diffusion
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What is an important factor in the pharmacologic responses elicited by the adrenergic receptors?
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The dynamic state of adrenergic receptors
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How are the density and sensitivity of alpha and beta-adrenergic receptors modulated?
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By the concentration of neurotransmitter or circulating hormone, for example increased plasma concentrations of norepinephrine results in decreased sensitivity or density, or both, of beta-adrenergic receptors in the cell membrane (i.e. down regulation)
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Where does the PNS have it cell bodies?
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In the brainstem and the sacral part of the spinal cord
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What forms the cranial outflow for the PNS?
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Cranial nerves three (oculomotor), seven (facial), nine (glossopharyngeal), and 10 (vagus)
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What forms the sacral outflow of the PNS?
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The intermediolateral gray horns of the second, third, and fourth sacral nerves
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What is the principal neurotransmitter released at the postganglionic fibers of the PNS?
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Acetylcholine, what other neurotransmitters such as vasoactive intestinal peptide also may be released
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What are postganglionic fibers of the PNS the release acetylcholine called?
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Cholinergic
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What are the postsynaptic receptor sites of the PNS?
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Nicotinic and muscarinic
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How is the action of acetylcholine at the synaptic site terminated?
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By acetylcholinesterase; a similar enzyme, pseudo-cholinesterase, is present in the plasma but does not appear to be physiologically important in terminating the action of acetylcholine
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Catecholamines
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Compounds with hydroxyl groups on the three and four positions of the benzene ring of phenylethylamine
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Endogenous catecholamines
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Include dopamine, norepinephrine, and epinephrine; which are synthesized in the nerve terminals of the sympathetic nervous system and the adrenal medulla
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Function of endogenous catecholamines
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To regulate most of the endogenous physiologic functions, especially during stress
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Synthetic catecholamines
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beside the endogenous catecholamines, there are number of synthetic catecholamines, most common being isoproterenol and dobutamine
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What do the pharmacologic effects produced by catecholamines reflect?
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The ability of these substances to stimulate adrenergic receptors
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Endogenous catecholamine administration
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All endogenous catecholamines are ineffective with oral administration because they are conjugated and oxidized in the G.I. mucosa and the liver
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How are catecholamines administered clinically?
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As continuous IV infusions to reduce desirable pharmacologic effects, predominantly in the cardiovascular system
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What is the immediate precursor of epinephrine and norepinephrine?
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Dopamine
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What is unique about dopamine among catecholamines?
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It is unique among sympathomimetic's because it has effects on multiple receptor sites depending on the dose
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Dopamine of low doses
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At doses of less than 3 µg/kilograms/min IV, dopamine stimulates D1 receptors which occur primarily in renal, mesenteric, and coronary beds
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What the stimulation of D1 receptors by dopamine lead to?
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Vasodilation and associated increases in renal blood flow, glomerular filtration rate, sodium excretion (also partially due to inhibition of aldosterone), and urine output
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What does dopamine do at higher doses?
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At doses of 3 to 10 µg per kilogram per minute IV, dopamine exerts a positive inotropic effect, i.e. beta-1 adrenergic effect, characterized by increased myocardial contractility without marked changes in heart rate or systemic blood pressure
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What else does dopamine do?
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It also evokes the release of endogenous stores of norepinephrine from nerve terminals, predisposes patients to cardiac dysrhythmias
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Dopamine at doses of 10 to 20 µg/kilograms/min IV
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At higher doses dopamine stimulates beta and alpha adrenergic receptors
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Dopamine the doses more than 20 µg/kilogram/min IV
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Stimulates alpha-1 adrenergic receptors, leading the vasoconstriction and significant increases in systemic blood pressure
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What can IV infusion of dopamine also do?
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Interfere with the ventilatory response to arterial hypoxemia, reflecting the role of dopamine as an inhibitory neurotransmitter at the carotid bodies
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What else can high doses of dopamine do?
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Inhibit the release of insulin, leading to hyperglycemia
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For what clinical use is dopamine most often used
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In the treatment of congestive heart failure, cardiogenic shock, and septic shock; these conditions are associated with decreased cardiac output, decreased systemic blood pressure, and increased left ventricular end – diastolic pressure, and oliguria, and dopamine because of its inotropic and chronotropic effects, increases stroke volume and cardiac output, improves systemic blood pressure, and reduces left ventricle size
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How is dopamine administered and why?
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Due to its rapid metabolism and must be administered as a continuous intravenous infusion, and because alkaline solutions may inactivate dopamine it is prepared in a solution of 5% glucose and water
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Extravasation of dopamine
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Like norepinephrine, extravasation of dopamine produces intense local vasoconstriction, which may be treated by local infiltration of phentolamine
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Fenoldopam
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A relatively selective postsynaptic D1 – agonist with no significant D2, Alpha, or beta-2 adrenergic effects
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Effects of low – dose infusion of fenoldopam
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At doses of 0.1 to 0.5 µg/kilograms/min, produces renal vasodilation and increased renal blood flow without changes and systemic blood pressure
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Higher doses of fenoldopam
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May decrease systemic blood pressure
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What is the principal use of fenoldopam
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As an IV antihypertensive drug
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Has a Renoprotective effect been established for fenoldopam?
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No
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Origination of norepinephrine
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Is liberated by postganglionic sympathetic nerves
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Action of norepinephrine
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Produces vasoconstriction and increases in systolic, diastolic, and mean arterial blood pressure
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What will norepinephrine due to heart rate?
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The increase in after load produces baroreceptor – mediated reflex bradycardia
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What is norepinephrine due to cardiac output?
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Cardiac output may be unchanged or decreased with an increase in coronary blood flow
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Clinical use of norepinephrine
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A continuous infusion may be used to treat profound systemic hypotension during shock or refractory hypotension as may occur in the early stages after ligation of the vascular supply to a pheochromocytoma
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Beta-2 – agonist effects of norepinephrine
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Are minimal
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What receptors does epinephrine stimulate?
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Alpha-1, beta-1, and beta-2
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What does low doses of epinephrine stimulates?
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Alpha-1 receptors in the skin, mucosa, and hepatorenal vasculature, producing vasoconstriction; whereas beta-2 – induced vasodilation predominates in skeletal muscle; the net effect being decreased systemic vascular resistance and a preferential distribution of cardiac output to skeletal muscles
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What does epinephrine do to renal blood flow?
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Renal blood flow is greatly decreased during infusion of epinephrine, even with unchanged systemic blood pressure
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Effect of epinephrine on beta-1 – receptors
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Stimulation of beta-1 – receptors increases heart rate and myocardial contractility, resulting in increased cardiac output, and because systemic blood pressure is not greatly elevated compensatory baroreceptor reflexes are not elicited, and cardiac output is increased
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What else does beta-1 – adrenergic stimulation do?
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Increases the automaticity of the heart, which manifests as cardiac irritability most often in the form of ventricular premature contractions
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What is unique about epinephrine amongst all the catecholamines?
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It has the most significant effects on metabolism, for example beta – adrenergic stimulation from epinephrine increases adipose tissue lipolysis and liver glycogenolysis, whereas alpha-1 adrenergic stimulation inhibits release of insulin from the pancreas
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What is a likely explanation for the hyperglycemia often observed in the perioperative period?
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Epinephrine release in response to surgical stimulation
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Clinical uses of epinephrine
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-To restore cardiac rhythm in patients with cardiac arrest and to treat refractory bradycardia
-as a continuous infusion to treat decreased myocardial contractility -subcutaneous epinephrine is used in combination with local anesthetics to decrease systemic absorption and provide local hemostasis -is the drug of choice in the treatment of life-threatening allergic reactions or for rapid relief of hypersensitivity reactions |
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Isoproterenol
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A synthetic catecholamine which acts as a nonselective beta – adrenergic agonist with no detectable effects on alpha-1 – receptors
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Infusion of isoproterenol
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Increases myocardial contractility, heart rate, systolic blood pressure, and cardiac automaticity, and it decreases systemic vascular resistance in skeletal muscles and in renal and mesenteric vascular beds, i.e. beta two – adrenergic effect; the result is an increase in cardiac output, a decrease in mean arterial pressure, and a significant increase in myocardial oxygen demands
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What may large doses of isoproterenol do?
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May cause tachycardia, diastolic hypotension, and a decrease in coronary blood flow leading the cardiac dysrhythmias, particularly in patients with ischemic heart disease
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Isoproterenol use for bronchospasm
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Although it does relieve bronchoconstriction and bronchospasm, it is largely been replaced by other highly effective beta two – selective sympathomimetic's
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Clinical uses of isoproterenol
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May be administered as a continuous infusion to increase heart rate after heart transplant, or as a chemical pacemaker in complete heart block
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In what specific patients might isoproterenol be selected?
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In patients with valvular heart disease in an attempt to decrease pulmonary vascular resistance
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Dobutamine
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A synthetic catecholamine obtained by substitution of a bulky aromatic group on the side chain of dopamine
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Racemic mixture of dobutamine
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Due to the center of asymmetry, dobutamine consists of a racemic mixture of positive and negative isomers
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Negative isomer of dobutamine
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Acts on A one – adrenergic receptors with pressor responses
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Positive isomer of dobutamine
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Is a potent beta – adrenergic receptor agonist and a potent alpha one – adrenergic receptor antagonist that blocks the effects of negative dobutamine
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What is the most prominent effect during infusion of dobutamine?
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At doses of 2 to 20 µg/kilograms/min IV there is a dose – dependent increase in cardiac output with a decrease or no change in systemic vascular resistance
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Inotropic effect
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Increases the force or energy of muscular contraction of the heart
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Chronotropic effect
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Increases the heart rate
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Argatroban
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Arginine derivative.
Mech: Selective competitive thrombin inhibitor. Monitor aPTT. Use: By IV for pts with HIT - dec. bad outcomes (tho still rather high) |
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Dobutamine used clinically
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Is used in combination with dopamine in treating systemic hypotension, especially in oliguric patients
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Dobutamine preparation
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Is prepared in 5% dextrose in water because it is inactivated in alkaline solutions
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Dopamine pharmacologic effects
(Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, renal blood flow, cardiac dysrhythmias) |
Mean arterial pressure: +
heart rate: + cardiac output: +++ systemic vascular resistance: + renal blood flow: +++ cardiac dysrhythmias: + |
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Preparation of dopamine (mg in 250mL)
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200 (800 µg/mL)
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Intravenous dose of dopamine (microgram/kilogram/min)
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2 - 20
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Pharmacologic effects of norepinephrine
(Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, renal blood flow, cardiac dysrhythmias) |
Mean arterial pressure: +++
heart rate: - cardiac output: - systemic vascular resistance: +++ renal blood flow: --- cardiac dysrhythmias: + |
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Preparation of norepinephrine (mg in 250 mL)
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4 (16 ug/mL)
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Intravenous dose of norepinephrine (microgram/kilogram/min)
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0.01 – 0.1
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Pharmacologic effects of epinephrine
(Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, renal blood flow, cardiac dysrhythmias) |
Mean arterial pressure:+
Heart rate: ++ Cardiac output: ++ Renal blood flow: -- Cardiac dysrhythmias: +++ |
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Preparation of epinephrine (mg in 250 mL)
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1 (4 ug/mL)
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Intravenous dose of epinephrine (microgram/kilogram/min)
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0.03 – 0.15
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Pharmacologic effects of isoproterenol
(Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, renal blood flow, cardiac dysrhythmias) |
Mean arterial pressure: -
heart rate: +++ cardiac output: +++ systemic vascular resistance: -- renal blood flow: - cardiac dysrhythmias: +++ |
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Preparation of isoproterenol (mg in 250mL)
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1 (4 ug/mL)
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Intravenous dose of isoproterenol (microgram/kilogram/min)
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0.03 – 0.15
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Pharmacologic effects of dobutamine
(Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, renal blood flow, cardiac dysrhythmias) |
Mean arterial pressure: +
heart rate: + cardiac output: +++ systemic vascular resistance: - renal blood flow: ++ cardiac dysrhythmias: - |
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Preparation of dobutamine (mg in 250mL)
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250 (1000 ug/mL)
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Intravenous dose of dobutamine (microgram/kilogram/min)
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2 – 20
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Sympathomimetic's
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Synthetic drugs obtained by dehydroxylation of hydroxyl groups at positions three and four on the benzene ring
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Use of sympathomimetics
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Mostly used as vasopressors or inotropes (ephedrine) to reverse the downward trend in systematic blood pressure during regional or general anesthesia
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Action of sympathomimetic's
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Act as alpha and beta adrenergic receptors by a direct effect at receptor sites or through an indirect effect by releasing endogenous norepinephrine
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What is the recommendation regarding prolonged administration of sympathomimetic's support systolic blood pressure?
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It is not recommended
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Common sympathomimetic's
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Ephedrine
phenylephrine metaraminol mephetermine methoxamine |
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How are sympathomimetic's classified?
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According to their selectivity for stimulating alpha or beta – adrenergic receptors, or both; alternatively they may be classified as direct acting, i.e. mimicking the effects of norepinephrine, or indirect acting, i.e. evoking the release of endogenous norepinephrine
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What are phenylephrine or methoxamine used for?
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When cardiac output is adequate, as in treating hypotension after spinal or epidural anesthesia or to increase coronary perfusion in patients with coronary artery disease or aortic stenosis without chronotropic side effects
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When his ephedrine more likely to be selected?
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When an increase in myocardial contractility is desirable
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What is a common adverse effect of sympathomimetic's?
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Cardiac dysrhythmias can occur in association with administration of the sympathomimetic which may reflect drug – induced beta – adrenergic stimulation
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So what is the disadvantage of using a sympathomimetic that lacks beta – adrenergic effects?
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Unopposed alpha – adrenergic receptor – induced peripheral vasoconstriction, resulting in increased diastolic blood pressure and associated baroreceptor reflex – mediated bradycardia and possible decreases in cardiac output
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Antihypertensives and sympathomimetic's
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Antihypertensives which decrease sympathetic nervous system activity may decrease the presser response elicited by an indirect – acting sympathomimetic, whereas a direct acting drug may be enhanced as receptors are sensitized (denervation hypersensitivity) by lack of tonic impulses
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What other classes of drugs have a high potential for adverse interactions with sympathomimetic?
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Tricyclic antidepressants or MAOIs which increase the availability of endogenous norepinephrine, for example administration of an indirect – acting drugs such as ephedrine can elicit an exaggerated systemic blood pressure response in patients being treated with TCAs or MAOIs
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When is this risk the worst?
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During the first 14 to 21 days of treatment with TCAs or MAOIs
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How should systemic hypertension be treated during this acute treatment with antidepressants?
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With peripheral vasodilators, but hypotension is better managed with the decreased dose of a direct – acting drug such as phenylephrine
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Sympathomimetic's after the acute treatment phase with antidepressants
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There seems to be down regulation of receptors and decreased likelihood of exaggerated systemic blood pressure responses after the acute treatment phase, and it is accepted that TCAs or MAOIs may be continued throughout the perioperative period without the introduction of unacceptable risk of adverse drug interactions
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Meperidine and MAOIs
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Has been reported to produce hypertensive crisis, convulsions, and, when used with MAOIs
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Ephedrine
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An indirect – acting sympathomimetic with alpha and beta – adrenergic agonist activity because it stimulates the release of norepinephrine and has some direct – acting effects
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What is unique about ephedrine?
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It is also effective after oral administration
|
|
|
Effects of ephedrine
|
Clinically cardiovascular effects resemble those of epinephrine, but it's systemic blood pressure elevating response is less intense than last about 10 min. longer
|
|
|
What does intravenous administration of ephedrine result in?
|
Systolic and diastolic blood pressure, heart rate, and cardiac output
|
|
|
Effect of ephedrine on systemic vascular resistance
|
Systemic vascular resistance may be altered minimally because vasoconstriction, i.e. A – adrenergic stimulation, in some vascular beds is offset by vasodilation, i.e. beta two – adrenergic stimulation, in other areas
|
|
|
Patients taking beta blockers and ephedrine
|
When given ephedrine patients taking beta blockers may show cardiovascular responses more typical of A – adrenergic stimulation
|
|
|
When is ephedrine commonly recommended for treatment of hypotension?
|
For the treatment of anesthesia – induced hypotension in pregnant women
|
|
|
What may occur with repetitive dosing of ephedrine?
|
Tachyphylaxis, presumably because of persistent block of adrenergic receptors, but may alternatively be from depletion of norepinephrine stores
|
|
|
What other adverse effects may ephedrine cause?
|
Beta – adrenergic stimulation by ephedrine may evoke cardiac dysrhythmias, especially in the presence of drugs that sensitize the heart to the effects of catecholamines
|
|
|
Phenylephrine
|
A direct – acting sympathomimetic that increases venous constriction more than arterial constriction (i.e. alpha-1 – adrenergic effect), it is less potent but longer acting the norepinephrine
|
|
|
Effect of phenylephrine on heart
|
Acutely, preload and after loader increased, with the net effect of an increased systemic blood pressure with reflex bradycardia and associated transient decrease cardiac output
|
|
|
Ephedrine receptor classification
(alpha-1, beta-1, beta-2) |
Alpha-1: ++
beta-1: ++ beta-2: + |
|
|
Is ephedrine direct or indirect acting?
|
Indirect (some direct)
|
|
|
Ephedrine IV dose
|
10 to 25 mg
|
|
|
Phenylephrine receptor classification
(alpha-1, beta-1, beta-2) |
Alpha-1: +++
Beta one: - beta-2: 0 |
|
|
Phenylephrine direct or indirect?
|
Direct
|
|
|
Phenylephrine IV dose
|
0.05 – 0.2 mg
|
|
|
Metaraminol receptor classification
(alpha-1, beta-1, beta-2) |
Alpha-1: +++
Beta one: ++ Beta two: 0 |
|
|
Metaraminol direct or indirect?
|
Indirect (some direct)
|
|
|
Metaraminol IV dose
|
1.5 – 5
|
|
|
Mephentermine receptor classification
(alpha-1, beta-1, beta-2) |
Alpha-1: +
Beta one: ++ beta-2: + |
|
|
mephentermine direct or indirect?
|
Indirect
|
|
|
mephentermine IV dose
|
10 – 25 mg
|
|
|
Methoxamine receptor classification
(alpha-1, beta-1, beta-2) |
Alpha-1: +++
beta-1: 0 beta-2: 0 |
|
|
Methoxamine direct or indirect?
|
Direct
|
|
|
Methoxamine IV dose
|
5 – 10 mg
|
|
|
What does elevated systemic blood pressure lead to?
|
Pathologic changes in peripheral arterial vasculature, leading the cardiac failure, renal insufficiency, and stroke
|
|
|
How are antihypertensives useful?
|
By selectively impairing sympathetic nervous system function at the heart and peripheral vasculature sites
|
|
|
Antihypertensives in the perioperative period
|
Because these drugs are continued during the perioperative period to maintain optimal control of blood pressure, there often is predominance of PNS tone, in response to sympathomimetic's may be modified
|
|
|
What does it mean if during anesthesia there is exaggerated decrease in systemic blood pressure, such as with hemorrhage positive airway pressure or sudden change in body position?
|
It may reflect an impaired degree of compensatory peripheral vasoconstriction
|
|
|
What are antihypertensives that acts centrally associated with?
|
Sedation and decreased anesthetic requirements (MAC)
|
|
|
Ace inhibitor use
|
In the treatment of essential hypertension, post-myocardial infarction (i.e. improved survival), and diabetic nephropathy, also to treat patients with CHF and mitral regurgitation due to their cardiac – remodeling and after load – reducing properties
|
|
|
Why do Ace inhibitors have improved patient compliance?
|
Because they have minimal CNS side effects, e.g. sedation and sexual dysfunction
|
|
|
Other unique thing about Ace inhibitors and side effects
|
Side effects associated with abrupt discontinuation antihypertensives, such as metabolic changes (e.g. hypokalemia, hyponatremia), rebound hypertension, bronchospasm, and CHF are not seen in patients treated with ace inhibitors
|
|
|
Mechanism of action of ace inhibitors
|
By blocking the conversion of angiotensin one to angiotensin two they prevent angiotensin two mediated vasoconstriction
|
|
|
Ace inhibitor effect on cardiac output
|
Cardiac output may remain normal or increase with filling pressure unchanged
|
|
|
What else to ace inhibitors results in?
|
Reductions in norepinephrine and plasma aldosterone level
|
|
|
What side effects are common among all Ace inhibitors?
|
Hyperkalemia and hypotension in hypovolemic patients
|
|
|
Captopril side effects
|
May cause reversible neutropenia, dermatitis, and angioedema
|
|
|
Enalapril side effects
|
Produces headache, dizziness, and syncope
|
|
|
Ace inhibitors in the perioperative period
|
Ace inhibitor therapy is generally continued until surgery and then re-initiated as soon as possible postoperatively, however there is concern about potential hemodynamic instability and hypotension in patients receiving Ace inhibitors in the preoperative.
|
|
|
What has been observed in patients being treated with ace inhibitors and undergoing general anesthesia for elective operations, especially if large blood or fluid shifts occur?
|
Prolonged hypotension
|
|
|
Clonidine
|
A centrally acting antihypertensive which stimulates alpha two – adrenergic receptors in the pontomedullary region of the CNS, which inhibits sympathetic nervous system activity leading to decreased outflow to the periphery, the net effect being reductions in cardiac output, systemic vascular resistance, and systemic blood pressure
|
|
|
Clinical use of acute administration of clonidine
|
Has been used to differentiate essential hypertension from suspected pheochromocytoma; unlike patients with pheochromocytoma the plasma concentration of norepinephrine in patients with essential hypertension is markedly suppressed
|
|
|
Clonidine and opiate use
|
Clonidine stops some of the adverse signs and symptoms of withdrawal from opioids and tobacco craving, it is speculated that it may replace opioid – mediated inhibition with alpha two – mediated inhibition of central sympathetic nervous system activity
|
|
|
What does preoperative administration of clonidine in small doses do?
|
Decreases the Mac of injected and inhaled drugs, presumably reflecting the sedative and anesthetic effects of this drug; clonidine also attenuates the sympathetic nervous system responses evoked by direct laryngoscopy and surgical stimulation
|
|
|
How long do the antihypertensive effects of clonidine last?
|
6 to 24 hours
|
|
|
Injection of clonidine into the epidural or subarachnoid space
|
Produces analgesia and unlike opioids does not produce depression of ventilation, pruritus, nausea, and vomiting; however it may produce bradycardia and sedation
|
|
|
What are the major adverse effects of clonidine?
|
Dry mouth, sedation, marked bradycardia, and contact dermatitis, which occur in 15% to 20% of patients treated with clonidine transdermal patch
|
|
|
What occurs in patients who abruptly discontinue clonidine before surgery?
|
Withdrawal symptoms, e.g. increased systemic blood pressure, during the pre-op in postoperative., Speculated mechanism for which is an acute increase in systemic vascular resistance because of the release of catecholamines
|
|
|
How can a rebound hypertension be controlled?
|
By maintaining clonidine therapy or by substituting alternative antihypertensive drugs, antihypertensives which act independently of central and peripheral nervous system mechanisms, e.g. peripheral vasodilators and ace inhibitors, do not seem to be associated with rebound hypertension after sudden discontinuation of chronic therapy
|
|
|
Minoxidil use
|
For the treatment of systemic hypertension and is refractive to other drugs
|
|
|
Minoxidil metabolism
|
Is metabolized in the liver to an active metabolite, minoxidil sulfate, which produces arteriolar vasodilation with no effect on venous capacitance vessels, which results in decreased systemic blood pressure, reflex tachycardia, and increased cardiac output to to an increase in venous return
|
|
|
What is minoxidil a potent stimulator of?
|
Renin secretion
|
|
|
Adverse effects of minoxidil
|
Include fluid and salt retention and reflex tachycardia with increased myocardial oxygen consumption; fluid retention can lead to pulmonary hypertension, reversible pericardial effusion, and cardiac tamponade
|
|
|
What is done to atomize the adverse effects of minoxidil?
|
It is often administered in combination with a beta – adrenergic antagonist and diuretics
|
|
|
Prazosin
|
A potent and selective alpha one – adrenergic receptor blocker in arterials and veins with minimal effects on alpha-2 – adrenergic receptors, which leads to a decrease in peripheral vasomotor resistance and decreasing venous return to the heart
|
|
|
In what patients is prazosin useful and why?
|
In CHF patients, because of after load reduction; it is also useful in preoperative preparation of patients with pheochromocytoma
|
|
|
What are the major side effects associated with prazosin?
|
Fluid retention and orthostatic hypotension
|
|
|
Hydralazine mechanism of action
|
Causes direct relaxation of arteriolar smooth muscle without any effect on venous smooth muscle, which leads to decreased systemic blood pressure, reflex tachycardia, and increased myocardial contractility due to sympathetic nervous system stimulation
|
|
|
What else does hydralazine do?
|
Increases plasma renin activity and causes fluid retention
|
|
|
Side effects of hydralazine
|
May produce hypotension, headache, flushing, tachycardia, and angina in patients with coronary artery disease; and prolonged use can produce drug – induced lupus syndrome, serum sickness, hemolytic anemia, and raptly progressive glomerulonephritis
|
|
|
When is hydralazine especially used to treat hypertension?
|
In pregnancy
|
|
|
Verapamil and diltiazem mechanism of action
|
Block calcium ion channels in cardiac cells, slowing heart rate, decreasing atrioventricular node conduction velocity, and increasing atrioventricular node refracroriness
|
|
|
When are calcium channel blockers useful?
|
For treating atrioventricular node reentrant tachycardia, and in reducing ventricular rate in atrial flutter and atrial fibrillation
|
|
|
In what other patients might these drugs be useful and why?
|
In CHF patients due to chronic essential hypertension because they produce peripheral vasodilation
|
|
|
The effects of what drugs will be potentiated by calcium channel blockers?
|
Neuromuscular blocking agents
|
|
|
What will occur when combining verapamil and a beta blocker?
|
Profound bradycardia and hypotension
|
|
|
Calcium channel blockers and the perioperative period
|
Calcium channel blocker treatment can be continued until the time of surgery without risk of significant drug interactions especially with respect to conduction of cardiac impulses
|
|
|
Labetolol
|
In antihypertensive that blocks A one – receptors selectively and beta – receptors non-selectively
|
|
|
What does blockade of alpha-1 – receptors do?
|
Decreases systemic vascular resistance and lowers systemic blood pressure without reflex tachycardia due to beta-1 – receptor block
|
|
|
How is labetolol eliminated?
|
Through the kidneys, elimination half – time is 5.5 hours, after conjugation with hepatic glucuronide
|
|
|
Forms of the labetolol
|
Is available in intravenous and oral forms
|
|
|
Clinical uses of labetolol
|
0.3 to 1 mg/kilogram IV is a safe and effective treatment for hypertensive emergencies in the perioperative period; it can also be used for sudden increases in heart rate and systemic blood pressure that result from abrupt increases in surgical stimulation in anesthetized patients
|
|
|
Treatment of acute hypertension due to exogenous phenylephrine or epinephrine overdose
|
Although labetolol has been recommended, the beta – blocking effects of this drug may be detrimental to the heart exposed to abrupt increases in after load, peripheral vasodilator drugs are preferable
|
|
|
Adverse effects of labetolol
|
May produce bronchospasm in asthmatics and CHF in patients with pre-existing cardiac dysfunction; may get withdrawal with abrupt discontinuation
|
|
|
Beta – adrenergic agonists
|
highly selective beta-2 – agonists, i.e. albuterol and terbutaline, produce relaxation of bronchial, uterine, and vascular smooth muscle, and their selectivity for beta-2 – receptors makes them less likely to produce adverse cardiac effects such as tachycardia or cardiac dysrhythmias
|
|
|
What adverse effect can beta-2 – agonists produce?
|
Reflex tachycardia, presumably caused by beta-2 – mediated vasodilation and subsequent hypotension
|
|
|
What else can occur with beta-2 – agonists?
|
Tachyphylaxis, which is attributed to the decreased number and sensitivity of beta – adrenergic receptors, i.e. down regulation, that occurs with chronic stimulation of these receptors
|
|
|
Albuterol
|
A highly selective beta-2 – agonist used in aerosol form for the treatment of bronchospasm in asthmatics and anesthetized patients, typically delivered by two or three deep inhalations 1 to 5 min. apart repeated every 4 to 6 hours
|
|
|
Dose of albuterol
|
Each metered dose aerosol delivers about 90 µg; the daily dose should not exceed 16 to 20 metered aerosol actuation
|
|
|
Ritodrine
|
A selective beta-2 – agonist, is infused to inhibit premature uterine contractions
|
|
|
Adverse effects of ritodrine
|
Include hypokalemia, hyperglycemia, tachycardia, and tachyphylaxis; hypokalemia most likely reflects sustained beta – adrenergic stimulation of the sodium pump with transfer of potassium ions intracellularly
|
|
|
Ritodrine and blood sugar
|
Persistent maternal hyperglycemia may evoke sufficient insulin release to cause reactive hypoglycemia in the fetus
|
|
|
Use of beta blockers
|
In the treatment of systemic hypertension, ischemic heart disease, CHF, and certain types of cardiac dysrhythmias
|
|
|
Action of beta blockers
|
May produce a selective beta-1 – adrenergic block, i.e. decreased heart rate and myocardial contractility, or may produce mixed responses: beta-1 and beta-2 – antagonism, i.e. bronchial and vascular smooth muscle contractions
|
|
|
What other characteristic do beta blockers such as propranolol possess?
|
Membrane – stabilizing activity
|
|
|
What is unique about certain beta blockers, e.g. pindolol and acebutolol?
|
They activate beta – receptors partially in the absence of catecholamines
|
|
|
On what system do beta – blockers have their major therapeutic effects?
|
The cardiovascular system
|
|
|
Action of beta – blockers
|
Decrease systemic blood pressure by slowing the heart rate and by decreasing myocardial contractility and cardiac output; they also attenuate baroreceptor – mediated increases in heart rate associated with vasodilator therapy
|
|
|
How was the last effect likely carried out?
|
Likely due to a decrease in the spontaneous rate of depolarization of cardiac pacemaker cells in slowing of conduction in the atrioventricular node
|
|
|
Do beta – blockers produce orthostatic hypotension?
|
No
|
|
|
Effect of beta – blockers on anesthetic requirements, i.e. Mac
|
Do not alter anesthetic requirements
|
|
|
Beta blockers and acute MI
|
It is recommended that all patients who experience acute myocardial infarction receive IV beta blockers as early as possible, these drugs are effective in relieving the symptoms of angina and in decreasing mortality after myocardial infarction by virtue of decreased heart rate, myocardial contractility, and myocardial oxygen requirements
|
|
|
Perioperative beta blocker recommendations
|
It is recommended to give perioperative beta blocker therapy to patients considered at risk for myocardial ischemia (e.g. patients with known coronary artery disease, positive preoperative stress tests, insolent – dependent diabetes mellitus, or left ventricular hypertrophy) during high – risk surgery (e.g. vascular surgery, thoracic surgery, intra-abdominal surgery, or surgery with anticipated large blood loss)
|
|
|
What is the goal heart rate for preoperative beta blocker therapy?
|
Resting heart rate between 65 and 85 bpm
|
|
|
What is the single most important potentially reversible risk factor for mortality and cardiovascular complications after noncardiac surgery?
|
Perioperative myocardial ischemia, so all beta blockers except those with intrinsic sympathetic nervous system activity decreased mortality; for example giving atenolol for seven days before and after noncardiac surgery in patients at risk for coronary artery disease may decrease mortality in the incidence of cardiovascular complications for as long as two years after surgery
|
|
|
Beta blockers given preoperatively
|
Beta blocker therapy can be initiated with atenolol 50 mg, bisoprolol 5 to 10 mg daily, or metoprolol 25 to 50 mg twice daily
|
|
|
What if the patient is seen the morning of surgery?
|
Give atenolol 5 to 10 mg IV or metoprolol 5 to 10 mg IV
|
|
|
Beta blocking during surgery
|
Give esmolol during surgery and postoperatively in the ICU
|
|
|
What are the common side effects associated with beta blocker therapy?
|
Fatigue and lethargy
|
|
|
What are the hazards of beta-adrenergic blockade?
|
Excessive myocardial depression and bronchoconstriction, additive myocardial depression can occur with volatile anesthetics but this is not clinically significant
|
|
|
Which beta blocker to select
|
-When bronchoconstriction is a possible response, as in patients with asthma or COPD, it may be useful to select beta blockers with selective beta-1 – blocking effects
-likewise cardio selective drugs would be a logical choice for patients with peripheral vascular disease to minimize the occurrence of vasoconstriction that accompanies beta 2 blockade -beta blockers with intrinsic sympathomimetic activity may be logical selections for treatment of patients with depressed left ventricular function or bradycardia |
|
|
Beta blockade in patients with partial or complete atrioventricular conduction defects
|
May produce life-threatening Brady dysrhythmias, this is particularly true in patients on calcium channel blockers such as verapamil
|
|
|
What metabolic abnormality might beta blockers accentuate?
|
They may accentuate increases in plasma concentrations of potassium associated with infusion of potassium chloride, presumably by interfering with the mechanism necessary for movement of this ion across cell membranes
|
|
|
Beta blockers in diabetic patients
|
Must exercise caution in using beta blockers in diabetic patients because warning signs and symptoms of hypoglycemia are blunted by beta blockade, plus cardio selective drugs are logical selections for patients with diabetes because suppression of insulin secretion is produced by beta 2 blockade
|
|
|
What is the initial drug recommended to treat signs of excessive drug – induced beta block, such as bradycardia or atrioventricular heart block?
|
Atropine
|
|
|
What if the signs of excessive beta blocker persist?
|
The specific treatment is administration of a beta adrenergic agonist such as isoproterenol or dobutamine, however it may be required to give large doses of these drugs to antagonize excessive data block; alternatively calcium chloride given intravenously 5 to 10 mg/kilogram IV antagonizes excessive data block independently of any known effect mediated by beta receptors
|
|
|
Discontinuation of beta blockers perioperatively
|
Abrupt discontinuation of beta blockers can be associated with excessive sympathetic nervous system activity manifesting as systemic hypertension in myocardial ischemia, presumably this reflects an increase in the number or sensitivity of beta-adrenergic receptors, i.e. up regulation, that occurs during chronic therapy
|
|
|
Treatment in this situation
|
Treatment with beta blockers should be maintained throughout the perioperative period, continuous IV infusion of esmolol could also be effective in maintaining beta blockade in those patients who cannot receive oral medications during the period
|
|
|
Peripheral vasodilators
|
Those given as an IV continuous infusion include sodium nitroprusside (SNP) and nitroglycerin (NTG)
|
|
|
Action of peripheral vasodilators
|
Both drugs decreased systemic vascular resistance by decreasing systemic vascular resistance, sodium nitroprusside, or by producing venous vasodilation thus decreasing preload, as in sodium nitroprusside and nitroglycerin
|
|
|
Nitroglycerin metabolism
|
Nitroglycerin is metabolized in the blood vessels to its active metabolite nitric oxide which activates guanylate cyclase to form cyclic guanine monophosphate and produce vasodilation
|
|
|
Sodium nitroprusside action
|
Like nitroglycerin increases intracellular nitric oxide that acts as an endogenous vasodilator
|
|
|
Potential toxic effects of sodium nitroprusside
|
Cyanide toxicity and methemoglobinemia
|
|
|
Adenosine
|
An endogenous nucleoside present in all cells of the body which is formed as a product of the enzymatic breakdown of adenosine triphosphate, is a potent dilator of coronary arteries and is capable of decreasing oxygen consumption by its anti-adrenergic and negative inotropic effects
|
|
|
Clinical uses of peripheral vasodilators
|
Are administered to treat hypertensive crises, to produce controlled hypotension, and to facilitate left ventricular forward stroke volume in patients with acute CHF or regurgitatant cardiac valve dysfunction
|
|
|
How does nitroglycerin compared to other vasodilators such as minoxidil and hydralazine?
|
Unlike the others nitroglycerin causes only modest increases in heart rate and an overall reduction in myocardial oxygen requirements
|
|
|
What clinically does nitroglycerin do
|
Decreases venous return and cardiac output by producing venous vasodilation
|
|
|
What clinical use does adenosine have?
|
At 6 mg IV is used clinically as an alternative to verapamil for treatment of paroxysmal supraventricular tachycardia
|
|
|
Nitric oxide
|
A novel cellular messenger important in cardiovascular, immune, and nervous system functions; inhalation selectively relaxes pulmonary vasculature, with improvement in arterial oxygenation and minimal systemic cardiovascular effects
|
|
|
In what patients as nitric oxide useful and why?
|
In managing patients with pulmonary hypertension because it lacks systemic effects due to its binding to oxyhemoglobin
|
|
|
When else is inhaled nitric oxide also used?
|
In diagnostic procedures such as determination of diffusion capacity across alveolar capillary membranes
|
|
|
Anticholinergic drugs
|
Include atropine, scopolamine, glycopyrrolate
|
|
|
Action of anticholinergics
|
Prevent the muscarinic effects of acetylcholine by competing for the same receptors as are normally occupied by acetylcholine
|
|
|
Sites of action of anticholinergics
|
Atropine and scopolamine are tertiary amines and can cross lipid barriers such as the blood brain barrier and placenta; in contrast glycopyrrolate acts principally on peripheral cholinergic receptors because it's quaternary ammonium structure prevents it from crossing lipid barriers and significant amounts
|
|
|
Doses necessary to produce anticholinergic effects
|
The sensitivity of peripheral cholinergic receptors differs so that low doses of an anticholinergic may be sufficient to inhibit salivation, but large doses are necessary for G.I. effects
|
|
|
antisialaggue effect
atropine, scopolsmine, and glycopyrrolate |
Atropine: +
scopolamine: +++ glycopyrrolate: ++ |
|
|
Sedative and amnesic effects
atropine, scopolsmine, and glycopyrrolate |
Atropine: +
scopolamine: +++ glycopyrrolate: 0 |
|
|
Increased gastric fluid pH
atropine, scopolsmine, and glycopyrrolate |
Atropine: 0
scopolamine: 0 glycopyrrolate: +/- |
|
|
Central nervous system toxicity
atropine, scopolsmine, and glycopyrrolate |
Atropine: +
scopolamine: ++ glycopyrrolate: 0 |
|
|
Relaxation of lower esophageal sphincter
atropine, scopolsmine, and glycopyrrolate |
Atropine: ++
scopolamine: ++ glycopyrrolate: ++ |
|
|
mydriasis and cycloplegia
atropine, scopolsmine, and glycopyrrolate |
Atropine: +
scopolamine: +++ glycopyrrolate: 0 |
|
|
anti-cholinesterases
|
Are represented by quaternary ammonium (e.g. neostigmine, pyridostigmine, edrophonium) and tertiary amine (e.g. physostigmine) drugs
|
|
|
Action of anti-cholinesterases
|
Inhibit the enzyme acetylcholinesterase (i.e. true cholinesterase) which is normally responsible for the rapid hydrolysis of acetylcholine after its release from cholinergic nerve endings, but in the presence of anti-cholinesterases acetylcholine accumulates at nicotinic and muscarinic receptor sites
|
|
|
site of action of anti-cholinesterases
|
Quaternary ammonia drugs cannot easily cross the blood brain barrier such that accumulation of acetylcholine is predominantly at peripheral sites such as the nicotinic neuromuscular junction, this is the principal mechanism for the drug – assisted antagonism of non-depolarizing neuromuscular blocking drugs; conversely physostigmine with its tertiary amine structure can cross the blood brain barrier making it an effective drug for treatment of central anticholinergic syndrome which manifests as emergence delirium in postanesthesia care unit
|
