ANS & Anticholinesterases Flashcards
Where is the parasympathetic nervous system origin?
Carniosacral origin CN III, V, VII, X
Sacral 2-4
What is the neurotransmitter for the sympathetic, parasympathetic and somatic systems?
Acetylcholine
What are the receptors for the autonomic nervous system?
Cholinergic–> nicotinic for all of the nervous systems and muscarinic for only the parasympathetic nervous system
What kind of action potential is acetylcholine?
Calcium mediated
What is acetylcholine made up of?
Choline and Acetyl CoA
What is acetylcholine deactivated by?
Acetylcholinesterase (choline and acetate)
What is the origin of the sympathetic nervous system?
Thoracolumbar T1-L2
How does acetylcholine work for the cholinergic neurons?
ACH binds with a post-synaptic receptor on the effector cell
ACH hydrolyzed by cholinesterase in the synaptic cleft
Choline is then recycled
What is the neurotransmitter for the adrenergic neuron?
Norepinephrine
What are the post-synaptic receptors for the adrenergic neuron?
Alpha1, Beta1, 2, and 3
Alpha2 as well but only in the CNS
What are alpha2 receptors in the PNS?
Presynaptic and inhibitory
What happens with norepinephrine with presynaptic terminal reuptake? Extraneurolan (effector cell) uptake?
Most is recycled, some is metabolized by MAO presynaptically.
Effector cell uptake, norepinephrine is metabolized by MAO and COMT
Which type of norepinephrine reuptake is important for endogenous catecholamines? Exogenous catecholamines?
Endogenous: Presynaptic terminal reuptake
Exogenous: minute amount drifts away, metabolized in the liver and kidney
How does norepinephrine work?
Dopamine enters the synaptic vessel
Dopamine beta hydroxylase converts dopamine to NE
An action potential releases NE from the synaptic vessel
Signal termination (reuptake, dilution by diffusion, metabolism)
What are the sympathetic neuron differences between blood vessels and the heart?
Blood vessels: almost no reuptake of NE, highest rate of synthesis
Heart: highest rate of reuptake
Drugs that alter ____ or ____ have more of an effect of BP. Drugs that affect ___ (___) have more of an effect on cardiac rate and rhythm
Biosynthesis
Storage
Reuptake
Cocaine
What are the co-neurotransmitters for a sympathetic neuron?
NE and ATP
What does NE and ATP act on?
P2 Purinoceptors & Alpha1 Adenoreceptors
What are P2 Purinoceptors?
Mediate fast component of contraction thru voltage dependent calcium channels
What are Alpha1 adenoreceptors?
NE sustains contraction of muscles through receptor operated calcium channels
How does ATP mediate contraction of muscle?
By acting on the P2x receptors through voltage dependent Calcium channels
How does NE sustain contraction of muscle?
By acting on the Alpha1 adenoreceptors through receptor operated calcium channels
What are neuromodulators?
Modify the process of neurotransmission
Where do neuromodulators work?
Prejunctionally and postjunctionally
Why do neuromodulators act prejunctionally?
To increase or decrease the amount of neurotransmitter released
Why do neuromodulators act postjuctionally?
To alter the extent or time course of the neurotransmitter effect
What does a Beta1 post-synaptic receptor do?
Increases adenylcyclase activity (cAMP)
Increases HR
Increases conduction velocity
Increases myocardial contractility
What does a Beta2 postsynaptic receptor do?
Stimulation leads to smooth muscle relaxation
Peripheral vasodilatation
Decreases BP
Bronchodilitation
Increases insulin secretion
Increases glycogenolysis and gluconeogenesis
Decreases GI mobility
How are Beta-2 receptors in the heart important for compensating for disease?
Help to maintain response to catecholamine stimulation as Beta-1 receptors are down-regulated during chronic catecholamine stimulation and CHF. NE usually activates beta1
What are the beta3 postsynaptic receptors?
Located on fat cells and suggest new therapy for obesity
What do the alpha1 postsynaptic receptors do?
Activation increases intracellular calcium Smooth muscle contraction Peripheral vasoconstriction Bronchoconstriction Inhibits insulin secretion Stimulates glycogenolysis and gluconeogenesis Mydriasis GI relaxation
What do alpha2 receptors do presynaptically in the PNS?
Inhibits adenylcyclase activity
Decreases entry of calcium into the cell
Limits the release of NE
What do alpha2 receptors do postsynaptically in the CNS?
Sedation
Decreased sympathetic outflow
Decreased BP
Ubiquitous substances that are both neurotransmitters and hormones
Catecholamines
Where are they hydroxyl groups located on catecholamines?
3 and 4 positions of the benzene ring
What are the catecholamines?
Dopamine NE Epi Isoproterenol Dobutamine
Drugs that act on adrenergic receptors can be classified as what?
Catecholamines and Synthetic non-catecholamines or sympathomimetics
What are all sympathomimetics derived from?
Beta phenylethylamine
T/F: All sympathomimetics are catecholamines. But not all catecholamines are sympathomimetics
False: all catecholamines are sympathomimetics but not all symptathomimetics are catecholamines
What do catecholamines act on?
Adrenergic receptors
How are catecholamines metabolized?
Rapidly inactivated my enzymes
Monaoamine oxidase (MAO): enzyme present in liver, kidneys, Gi tract that catalyzes oxidative deamination
Catechol-o-transferase (COMT): methylates the hydroxyl group of catecholamines
Naturally occurring catecholamines (endogenous)
Sympathomimetics
What do indirect-acting synthetic non-catecholamines do?
Release endogenour neurotransmitter NE from postganglionic sympathetic nerve endings
What are the indirect-acting synthetic non-catecholamiens characterized by?
Mostly alpha and beta1 adrenergic effects because NE is a weak beta2 agonist
What is denervation or depletion of a neurotransmitter?
As with repeated doses of a sympathomimetic, blunts the pharmacologic responses normally evoked by the drug
What are the direct acting synthetic non-catecholamines?
Phenylephrine and methoxamine
What do direct acting synthetic non-catecholamines do?
Activate adrenergic receptors directly
T/F: synthetic noncatecholamines are less potent than catecholamines
True
T/F: Denervation or depletion of neurotransmitters prevents the activity of phenylephrine and methoxamine
False, does not prevent
Receptor is a specific protein molecule in the lipid bilayer
Effector cell receptor
What happens when an effector cell receptor is bound?
It interacts with guanine nucleotide proteins (g proteins)
How are G proteins activated?
GTP is hydrolyzed to GDP activating g proteins that can interact with effector systems
What are the 2 types of control for effector cell receptors?
Down regulation and up regulation
What is down regulation?
Extended exposure to agonists reduces the number, but not their response. Results in tachyphylaxis
What is up regulation?
Chronic depletion of catecholamines or use of antagonists increases the number of receptors but not their sensitivity. May account for w/d syndrome with beta blockers
What is receptor uncoupling?
Occurs rapidly (seconds to minutes) Inability of the receptor to bind G protein (alters the function of the receptor) Uncouples the receptor from the signal transduction system. Caused by the phosphorylation of the receptor and possibly the G protein
What is sequestration?
Occurs more slowly (minutes to hours)
Movement of receptors from the cell surface to intracellular compartments
Not accessible to hydrophilic ligands
What is downregulation?
Prolonged process (hours to days) Movement of receptors from the cell surface to intracellular compartments but then destroyed Receptors are not available for recycling to the cell surface. New receptor protein must be made from RNA to replace lost receptors (ex: from chronic stress or CHF)
What is desensitization?
The reduction in a physiologic response to a stimulus that is constant overtime
Interact with a receptor and cause an effect to occur
Agonist
Interact with a receptor but prevents intracellular events from occurring. Inhibit in a competitive manner
Antagonist
What is stroke volume?
Blood ejected in 1 cardiac cycle
What is stroke volume determined by?
Preload, afterload and contractility
What are the 2 types of anticholinesterase drugs?
Tertiary amines and quaternary amines
What drugs are tertiary amines?
Physostigmine
What drugs are quaternary amines?
Edrophonium
Neostigmine
Pyridostigmine
Which anticholinesterase drugs cross the blood brain barrier?
Tertiary amines and are used for nonspecific antagonism of the CNS effects of certain drugs
What actions do anticholinesterase drugs do?
Enzyme inhibition
Presynaptic effects
Direct effects
How does enzyme inhibition work for anitcholinesterases?
Inhibit acetylcholinesterase which results in increased availability of ACh
Where does the increased availability of ACh happen for enzyme inhibition for anticholinesterases?
Neuromuscular junction
Muscarinic receptors
Autonomic ganglia (sympathetic and parasympathetic)
What is a true cholinesterase and is responsible for the hydrolysis of ACh to choline and acetic acid?
Acetylcholinesterase
How does neostigmine and pyridostigmine work for enzyme inhibition?
Hydrolized by acetylcholinesterase
Carbamylates the enzyme in the process
Block enzyme’s ability to hydrolyze ACh
How does edrophonium work for enzyme inhibition?
Forms a reversible electrostatic attachment
How do anticholinesterase drugs work for presynaptic effects?
In the absence of neuromuscular blockers, acetylcholinesterase inhibitors may produce fasiculations
How do anticholinesterases work for direct effects?
At doses greater than usual clinical doses, anticholinesterase drugs have been reported to produce some form of neuromuscular blockade. Excess ACh desensitizes the NMJ
How are anticholinesterase drugs classified?
Reversible inhibition
Formation of Carbamyl Esters
Irreversible Inhibition
What is reversible inhibition for anticholinesterases?
Electrostatic attachment to the anionic site (Edrophonium)
What is formation of carbamyl esters?
Reversible formation of carbamyl ester complexes at the esteratic site
What is irreversible inhibition of anticholinesterases?
Organophosphates combine with the esteratic site to form a stable inactive complex
What is edrophonium’s predominant site of action?
Presynaptic
What is the most important determinant of relative potency for anticholinesterases?
Affinity
What is the onset of action for Edrophonium, Neostigmine and Pyridostigmine?
Edrophonium: 1-2 minutes
Neostigmine: 7-11 minutes
Pyridostigmine: up to 16 minutes
What is the duration of action for the quaternary amines?
t1/2: 60-120 minutes
What are the muscarinic effects of anticholinesterases?
Bradycardia, salivation, bronchoconstriction, miosis, hyperperistalsis and increased risk of PONV
What are the nicotinic effects of anticholinesterases?
Act at the neuromuscular junction and autonomic ganglia
Which drugs produce marked inhibition of plasma cholinesterase?
Neostigmine and pyridostigmine
T/F: muscarinic effects occur at a lower concentration of ACh than nicotinic effects
True
What are the clinical uses of anticholinesterases?
Antagonist-assisted reversal of neuromuscular blockade
Treatment of CNS effects of certain drugs
Treatment of myasthenia gravis
Treatment of Glaucoma
How do anticholinesterases work for treatment of myasthenia gravis?
Increase ACh at the neuromuscular junction
How do anticholinesterases work for reversing neuromuscular blockade
Increase the availability of ACh at the NMJ
Acts presynaptically and postsynaptically
Tips the balance of competition between ACh and NMB in favor of ACh and restores neuromuscular transmission
What is the dosage for edrophonium? Neostigmine? Pyridostigmine?
Edrophonium: 0.5 mg/kg
1 mg/kg (twitch height <10%)
Neostigmine: 0.043 mg.kg
Pyridostigmine: 0.21 mg/kg
For anticholinesterase drugs, what does potency depend on?
NMB being antagonized
Speed of spontaneous recovery
Depth of NMB when the reversal is initiated
End point selected
What do you mix Edrophonium with for an anticholinergic?
Atropine 7 mcg/kg
10-15 mcg/kg is opioid based technique
What do you mix Neostigmine with for an anticholinergic?
Atropine 20 mcg/kg
Glycopyrrolate 10 mcg/kg
When do you administer reversal?
Administer reversal only after twitch height has recovered to >10%, otherwise keep patient sedated and intubated
What factors influence reversal of neuromuscular blockade?
NDMR being reversed
Intensity of the blockade at the time of reversal
Antagonism of neuromuscular blockade may be inhibited or prevented by what?
Certain antibiotics Hypothermia Resp acidosis Hypokalemia and metabolic acidosis Edrophonium less effective in reversing deep NMB (twitch height <10%) Atracurium: edrophonium may be better Vecuronium: neostigmine may be better
What is the standard of care for patients receiving NMBs?
Neuromuscular monitoring
What is adequate neuromuscular recovery?
TOF ratio >0.9
What are some potential consequences of postop residual blockade?
Adverse resp events such as upper airway obstruction, inadequate ventilation, hypoxemia, paralysis of laryngeal muscles and aspiration pneumonia and atelectasis
Why is the incidence of residual block so high?
Lack of monitoring
Lack of reversal of neuromuscular blockade
Use of excessive large doses (which could be addressed by monitoring)
What are some limitations of using Neo to reverse neuromuscular blockade?
Slow onset
Inadequate reversal of deep block
Risk of arrhythmias
Because of CV risk, must be combined with other drugs such as glycol or atropine
What is the first selective binding agent to reverse neuromuscular blockade and reverses steroid-based neuromuscular blockers
Sugammadex (modified gamma-cyclodextrin)
What does Sugammadex do to Rocuronium?
Strongly binds and encapsulates Rocuronium making it unavailable to the NMJ. Reverses neuromuscular blockade without relying on acetylcholinesterase inhibition
What are the characteristics of Sugammadex that differentiate it from Neostigmine?
MOA: reverses NMB without relying on ACTH
Specific aminosteroidal non-depolarizing muscle relaxants
Lack of CV side effects, does not require atropine or glycol
Ability to reverse profound block
Reverses block more quickly
Physostigmine is used to reverse what?
Anticholinergic drugs
Opioids
Benzos
Anesthetics
How do Anticholinesterases work for the treatment of Myasthenia Gravis?
Increase the response of skeletal muscles to repetitive impulses by increasing available ACh
What does a cholinergic crisis manifest as?
Skeletal muscle weakness
What does an acute overdose of anticholinesterase manifest as for muscarinic effects?
Miosis and difficulty focusing Salivation Bronchoconstriction Bradycardia Abdominal cramps Loss of bowel and bladder control
What are the nicotinic and CNS effects of acute overdose of anticholinesterase overdose?
Skeletal muscle weakness to paralysis and apnea Confusion Ataxia Seizures Coma Depressed ventilation
What are organophosphate anticholinesterases?
Insectisides and nerve agents
Rapidly absorbed throught the skin, GI tract and across alveoli
High lipid solubility ensures that they will cross the BBB and produce intense CNS effects
What is the treatment of an overdose of anticholinesterase drugs?
Atropine for antimuscarinic effects
Pralidoxime (Acetylcholinesterase reactivator)
Supportive measures
