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150 Cards in this Set
- Front
- Back
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What system is typified by a single neuron axon from the spinal cord to the skeletal muscles?
What receptors are at the target organ? |
Somatic Motor System
nicotinic receptors. |
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What are the 2 major anatomical functional divisions of the ANS?
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Sympathetic and Parasympathetic Nervous Systems.
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What is the primary fx of the ANS?
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Autonomous control of activity at heart, smooth muscles, lungs and glands.
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What is the overall basic design of the ANS?
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A two-neuron system with preganglionic and postganglionic neurons (with a few exceptions to that rule).
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The PNS arises from what nerves?
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Craniosacral.
Cranial Nerver (CN) III - oculomotor, CN VII (Facial), CN IX (Glossopharyngeal), CN X (Vagus), and S1-S3 spinal nerves. |
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In the PNS, the preganglionic axons synapse with postganglionic neurons where? In what ratio?
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Near the effector organ....preganglionic nerves tend to be long in the PNS. They synapse in a 1:1 ratio.
Ach to a nicotinic receptor (Sympathetic = Short, Parasympathetic = Long) |
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What NT do the preganglionic nerves of the PNS release? How about the postganglionic?
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Both release Ach
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All preganglionic neurons of the SNS and PNS release what NT?
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Ach to a nicotinic receptor
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In what system are the Muscarinic receptors located?
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In the postganglionic PNS AND at sweat glands in the postganglionic SNS
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Do ANY preganglionic neurons of the PNS or SNS synapse with an effector organ?
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Yes, the preganglionic SNS fibers that synapse directly with nicotinic receptors on the adrenal medulla. No postganglionic neurons involved here.
(The adrenal medulla in effect IS the postganglionic neuron). |
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Through what mechanism do muscarinic receptors exert their effects?
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Via G-protein coupled receptors.
Gi is stimulated, inhibiting adenylate cyclase and the formation of cAMP |
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How do nicotinic receptors exert their effects?
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via ligand-gated ion channels (Na+, K+ channels)
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From where do the preganglionic neurons of the SNS arise?
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from the thoracolumbar segment of the spinal cord.
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What portions of the SNS release AcH?
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All preganglionic neurons secrete Ach to nicotinic receptors.
The preganglionic neurons that synapse directly with nicotinic receptors on the adrenal medulla. The postganglionc fibers that ennervate muscarinic receptors of exocrine and sweat glands. |
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What is the ration of preganglionic to postganglionic fibers in the SNS?
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1:20 - for a FAST effect (fight or flight!)
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What NT do most postganglionic neurons of the SNS release?
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norepinephrine; (the adrenal medulla releases epi + a little norepi)
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Let summarize: where are all the cholinergic neurons in the ANS?
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All PREganglionic neurons of the ANS.
All POSTganglionic neurons of the PNS. Postganglionic SNS neurons synapsing with a muscarinic receptor on exocrine/sweat glands & piloerector muscles. Preganglionic SNS neurons synapsing directly with nicotinic receptors on the adrenal medulla. |
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All post-ganglionic cholinergic receptors of the PNS are __________.
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All post-ganglionic cholinergic receptors of the PNS are muscarinic.
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What is the postganglionic NT of the SNS?
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Norepinephrine
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What are the adrenergic receptors of the SNS postganglionic neurons?
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Alpha 1 & 2; Beta 1 & 2
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What is the effect of activating a Beta 1 adrenergic receptor?
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Activation of a Beta 1 receptor increases ALL cardiac functions.
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What is the effect of activating an alpha 1 adrenergic receptor?
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Contraction of smooth muscle:
Radial muscle contraction: Mydriasis GI and urinary Sphincter contraction Vasoconstriction Ejaculation |
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What is the effect of activating a Beta-2 adrenergic receptor?
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Relaxation of smooth muscle
bronchodilation Relaxation of the uterus Vasodilation of skeletal muscle vascular beds. (activation of muscle spindle fibers) |
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What receptors to Norepinephrine, Epinephrine and Dopamine bind to respectively?
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Norepinephrine: alpha 1, beta 1 & (alpha 2)
Epinephrine: Alpha 1 , Beta 1 & 2, (alpha 2) Dopamine: (at high doses dopamine mimics NE because it is a precursor) Low dose - D1 Mod dose - D1, Beta 1 Hi dose - Beta 1, Alpha 1 |
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What types of muscle does activation of alpha 1 receptors cause CONTRACTION in?
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Smooth muscle:
Vascular - vasoconstriction and increase in BP Radial eye muscle - causes contraction and mydriasis (dilation) Vas deferens, prostate Sphincters of GI and urinary |
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Alpha 1 receptors can be stimulated by what NTs?
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Norepi, Epi and Hi-dose dopamine.
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Beta 1 receptors can be stimulated by what NTs?
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Norepi, Epi and Moderate to Hi-dose dopamine
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Beta 2 receptors can be stimulated by what NTs?
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Epinephrine (so s/t adrenal stimulation and release of epinephrine)
NOTE: Beta 2 activation is NOT due to Norepi. |
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Does the SNS or PNS exert dominant control over the vasculature?
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SNS...directly via alpha 1 receptors on resistance and capacitance vessels; indirectly via epi-mediated beta-2 stimulation on vasculature of skeletal muscle beds.
The PNS has some vestibular M3 receptors that cause some vasodilation (on the penis) but nowhere else. |
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Compare and contrast exocrine functions of sweating and secretions.
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Increased sweating is a SNS mediated fx.
Increased secretions is a PNS mediated function. Both are controlled by muscarinic 3 receptors. |
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Mydriasis (dilation) of the pupil is mediated by what?
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stim of postganglionic SNS alpha-1 receptors on the dilator pupillae/radial muscle of the eye causing contraction.
Pregang nerve arises from the intermediolateral horn of spinal cord. |
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Miosis (constriction) of the pupil and accomodation for near vision is mediated by what?
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stim of Postganglionic PNS M3 receptors causes sphincter muscle constriction (miosis) and ciliary muscle contraction (accomodation).
Pregang nerve arises in the Edinger-Westphal ciliary ganglion. |
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PNS mediated contraction of teh ciliary muscle in the eye also does what?
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Mechanically opens the trevecular mesh and allows aqueous humor to flow out down Canal of Schlemm
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What is the purpose of an adrenergic agonist?
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To enhance activity and alpha or beta receptors.
Sympathomimetric |
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Are nicotinic compounds selective?
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Not really - they hit the preganglionic NT receptors in both branches of the ANS.
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Acetylcholine has a quaternary ammonium compound on one end. What is the significance of this?
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This is a charged molecule. It cannot cross the BBB due to its ionic state. Ach in the brain is produced and secreted by neurons in the brain. (There are muscarinic and nicotinic receptors in the brain.)
Drugs that mimic Ach usually also are charged and therefore have no CNS effects. (This also means it is usually excreted renally and has a poor F.__ |
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How is Ach formed?
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Choline + Acetyl coenzymyme A ---(choline acetyltransferase/CAT)---> Ach
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What is the rate limiting step in Ach synthesis?
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The rate of choline reuptake by the cells
(after Ach breakdown in the synapse) |
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What is the enzyme that catalyzes the hydrolysis of Ach into acetate and choline in the synaptic cleft?
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Acetylcholinesterase
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Where is AchE found?
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in the NM jx, at postganglionic parasympathetic synapses (effectors) and at autonomic ganglia
(in contrast...pseudocholinesterase is found in the plasma, liver, and glial cells...so it takes longer to metabolize Sux because Sux must diffuse away from the NM junction and into the plasma to be hydrolyzed) |
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What happens when AchE is blocked/inhibited?
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There is an increase in the Ach available to bind to Nicotinic and Muscarinic receptors.
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Explain the Mechanism of Action of Botulinum Toxin.
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Botulinum toxin inhibits ACh...decreasing firing at the NM junction and muscle weakness/ paralysis. (Flaccid paralysis).
It is used locally, but if a systemic dose is given it will decrease action at all the ANS preganglionic neurons - that is a bad thing. (Can cause loss of autonomic tone). Uses: Local injection Strabismus Blepharospasm |
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Explain the mechanism of action of Latrotoxin.
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Latrotoxin (in black widow spider venom) increases ACh release. This will cause muscle tetany and painful spasms. (contraction).
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How is the effect of ACh terminated?
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By degradation - hydrolysis reactions catalyzed by AChEs. (IN THE SYNAPTIC CLEFT)
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What happens if you inhibit Ach release systemically?
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Your ANS stops. Loss of autonomic tone. That is bad...very bad.
HOTN, etc |
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What two esterases break down ACh in the body? Where are they found?
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AChE - NM junction, postganglionic PNS synapses, autonomic ganglia.
Pseudocholinesterase/Butyryl cholinesterase: plasma, liver, glial cells --> this metabolizes drugs that look like ACh. |
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T/F: cholinergic receptors are found on all post-synaptic sites on effector organs innervated by the PNS.
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TRUE
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Where, in addition to all post-synaptic sites on effector organs innervated by the PNS, are cholinergic receptors found in the body?
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-Post-synpatic sites to sweat gland innervated by the SNS cholinergic fibers. (M3)
-ALL post-synaptic sites on skeletal muscle (N) -ALL autonomic ganglia including the adrenal medulla (N) -Blood vessels (M3) (vestibular except for penis) |
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Differentiate between the locations of Nicotinic and Muscarnic receptors.
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Nicotionic: neuromuscular jx of striated muscle, all autonomic ganglia, adrenal medulla
Muscarinic: Parasympathetic effector organs, sweat gland (SNS cholinergic fibers), blood vessels, CNS |
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Except for muscarinic recpetors on ______ and _______, activation of muscarinic receptors is the same as parasympathetic activation.
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Except for muscarinic recpetors on sweat glands and blood vessels, activation of muscarinic receptors is the same as parasympathetic activation.
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T/F: Activation of muscarinic receptors of heart increases rate of depolarization.
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FALSE: The general resposne to muscarinic receptor activation is hyperpolarization of heart muscles (decrease cAMP and open Cl ion channels, making the inside more negative) and a decrease in the rate of depolarization.
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What are the two subtypes of Nicotinic receptors?
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1) neuromuscular nicotinic receptors (skeletal muscle)
2)ganglionic nicotine receptors (autonomic ganglia & adrenal medulla) |
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Are both subtypes of nicotinic receptors ligand gated ion channels?
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yes
(Na and K ions flow in and out) |
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What is the difference in the response evoked by activation of neuromuscular nicotinic vs ganglionic nicotinic receptors?
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Neuromuscular: NM nicotinic receptors open the Na+ channel and cause depolarizing end plate potential (EPP) to trigger muscle action potential & contraction.
Ganglionic: FAST!!! Activation of ganglionic nicotinic receptors cause a rapid excitatory post synaptic potential (EPSP) |
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What happens in a depolarizing block?
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Way too much agonist is present. The ion channel gate is open, but never gets back to a closed-ready state. It is like flooding the engine of a car.
CANNOT be reversed by adding more agonist. You have to decrease the amt of agonist to reverse. Ex: Cholinergic crisis - progressive weakness |
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If you give a muscarinic agonist, what does it look like?
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Activation of the PNS.
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What are the basic muscarinic actions?
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M2: Bradycardia
M3: ---> Lungs: Broncoconstriction and increased glandular secretions --->GI: Increased glandular secretions, relaxed spinchters, and increased contraction of smooth muscle to increase GI and urinary motility. Contract the urinary detrusor muscle and relax the urinary sphincter. ---> Sweat Glands: activate ---> Penis: Erection via NO and VD ---> Eye: Contract Sphincter and Ciliary muscles causing miosis and accomodation (increased outflow of aqueous humor) ---> Activate all exocrine glands. |
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What happens to glandular activity when you get a muscarinic agonist on board?
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All glandular secretions increase when muscarinic agonists are on board.
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What are the two classes of muscarinic receptor agonists?
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Choline esters -(acetycholine/Miochol; Bethanecol/Urecholine)
Natural Cholinomimetic Alkaloids - (Pilocarpine, Muscarine) |
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The choline ester Bethanechol (Urecholine) is primarily metabolized by what mech?
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Pseudocholinesterase; it is resistant to ACh hydrolysis.
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What are some benefits of Bethanechol?
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Not many CV effects,; not much vasodilation x at high doses & NO nicotinic effects.
Useful for contraction of smooth muscle of GI tract and bladder. |
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Are the natural cholinomimetic alkaloids (Pilocarpine and Muscarine) nicotinic or muscarinic agonists or bot?
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Purely muscarinic.
M-selective. |
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What are the two types of glaucoma?
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Narrow angle/angle closure glaucoma: ocular emergency..can be caused by massive dilation of the pupil. Closes the canal, preventing drainage of AH.
Open-angle/wide angle/chronic simple glaucoma: chronic permanent condition. Ciliary body produces too much Aqueous Humor (controlled by Beta receptors). Normally, aqueous humor is produced in the ciliary body of the eye and exits out the canal of Schlemm (b/n the iris and the cornea). IOP increases either because of too much aqueous humor production or because of decreased AH outflow. The pressure starts to crush the axons of the retina as they exit out of the back of the eye. You start to go blind. Peripheral vision goes first and then it leads to blindness. |
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How do muscarinic receptor agonists help in tx of glaucoma?
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Ach binds to M3 receptors on ciliary muscle, contracting ciliary muscle (accomodation). This opens the canal of schlemm, allowing aqueous humor to drain out.
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What are some uses for muscarinic agonists pharmacologically?
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EYE: operations requiring miosis (constriction); tx of glaucoma. Pilocarpine
GI: increase tone & motility; tx of postop abd distention, gastric atony/paralysis. Bethanecol Urinary Bladder: Increase tone and motility. Tx for urinary retention/inadeq bladder emptying postop/postpartum, hypotonic bladder. Bethanecol. Xerostomia: induce salivation; drymouth s/t radiatino tx or Sjorgen's syndrome. Pilocarpine. |
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Should you give Bethanecol if you suspect there is a blockage or obstruction (like a tumor or section of necrotic gut?)
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No
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What are the s/sx of M agonist OD?
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Sweating and excessive parasympathetic activation. MIosis, accomodation spasms, bladder spasms, IBS
Could have a cholinergic crisis as well. |
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What is the tx for muscarinic OD?
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Muscarinic antagonist: atropine, glycopyrolate
AND Epi for severe cardiac symptoms |
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What are two types of parasympathomimetics?
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Muscarinic Receptor Agonists
Acetylcholinesterase Inhibitors |
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AChE inhibitors block what enzymes?
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Both AChase and PChase
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What are the actions of a ACh-ase inhibitor?
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Increased parasypathomimetic activity + increased sweat gland activity.
Increased Nicotinic responses at the autonomic ganglia Muscles twitches from Ach at NM Junction. CNS effects (some do cross BBB) (With an OD...you can have a phase 1 deplolarizing block all over - Cholinergic crisis..weakness and then flaccid paralysis/ autonomic paralysis...in this case, all the original effects of the AchI will stop. ) |
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Acetylcholinesterase performs what action?
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Hydrolyzes ACh into Choline + Acetic acid.
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What are the three classes of AChE inhibitors?
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REVERSIBLE - binds to anionic site of active center with no interaction with esteratic site. Actions are brief and reversible. Rapidly eliminated. Edrophonium is the only reversible AchEI.
SLOWLY REVERSIBLE: Carbamates. Carbamylated-enzyme intermediate if fairly stable. Neostigmine, Physostigmine, Donepezil, & Carbaryl (an insecticide). IRREVERSIBLE: Organophosphates: Produces a very stable phosphorylated enzyme intermediate. (Echothiophate Parathion, malation (insecticides), Nerve gases) |
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If AChE inhibitors increase the amount of ACh available at the synapse, then why is there sometimes inhibition at the nicotinic receptors of the autonomic ganglia & skeletal muscle?
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Depolarization block (when there is too much Ach)...
There is initial excitation of autonomic ganglia followed by inhibition d/t the block. In SM, there is an initial muscle contraction followed by depol block. |
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What happens in the CNS at higher doses of AChE inhibitors?
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CNS Activation followed by CNS depression:
First: confusion, ataxia, slurred speech, lost reflexes Then: convulsions, coma and respiratory paralysis |
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What are the Three Main Effects/ Uses of Acetylcholinesterase Inhibitors (Drugs)?
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Parasympathomimetic effects...by increasing the amount of ACh to bind to muscarinic/ nicotinic receptors.
1 - GI/ Urinary: increased tone and activity 2 - Eye: Intraocular agents force miosis or accomodation to decrease IOP. 3 - Increased activity at the NM Junction for weakness |
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What are the CV effects of AChE inhibitors?
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AChEs cause activaton of PNS M receptors AND SNS preganglionic (N) receptors.
The effects are complex. |
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Do AChE inhibitors increase or decrease sweat gland activity?
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Increase - more ACh available at synapse of SNS cholinergic fibers (apparently depol blockade does not happen here)
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What are the 6 main thx uses of cholinesterase inhibitors?
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EYE: tx of glaucoma; echothiopate & physostigmine
GI/URINARY: tx of atony of GI tract & urinary bladder smooth muscle. (DO NOT use in case of peritonitis, obstruction, or questionable GI viability). MYASTHENIA GRAVIS: Neostigmine REVERSAL OF NEUROMUSCULAR BLOCKADE TX FOR INTOXICATION w/MUSCARINIC ANTAGONISTS (e.g. - atropine, glycopyrolate) & OTHER DRUGS WITH ANTIMUSCARINIC ACTIVITY (tricyclics, phenothiazines, some H1 receptor antagonists); Physostigmine (counteracts antimuscarinic CNS effects) TX OF ALZHEIMER'S: Donazepil/Aricept |
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What are the CV effects of AChE inhibitors?
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AChEs cause activaton at postsynaptic PNS site AND activation of symp & parasymp ganglia - the effects are complex.
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T/F: sx of AChE inhibitor intoxication will/can include Muscarinic, Nicotinic and CNS sx.
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TRUE
(IF it's one that crosses the BBB). Musarinic: Increased GI and urinary motility, increased sweat gland activity, Bradycardia, Sphincter and Ciliary muscle contraction, Decreased IOP Nicotinic: SNS activation, muscle tremors, CNS: CNS activation and then depression. |
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Do AChE inhibitors increase or decrease sweat gland activity?
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Increase - more ACh available at synapse of SNS cholinergic fibers (apparently depol blockade does not happen here)
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What are the Muscarinic sx of AChE inhibitor toxicity?
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SLUDGE-BAM
S-salivation, sweating L-Larcrimation (tearing) U-Urination D-Defecation G-GI cramps E-Emesis B-Bronchoconstriction & bradycardia. A-Accomodation (spasm) M- Miosis or Muscle-twitches/fatigue - nicotinic) |
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What are the 6 main thx uses of cholinesterase inhibitors?
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EYE: tx of glaucoma; echothiopate & physostigmine
GI/URINARY: atony of GI tract & urinary bladder smooth muscle. MYASTHENIA GRAVIS: Neostigmine REVERSAL OF NEUROMUSCULAR BLOCKADE TX FOR INTOXICATION w/MUSCARINIC ANTAGONISTS (e.g. - atropine, glycopyrolate) & OTHER DRUGS WITH ANTIMUSCARINIC ACTIVITY (tricyclics, phenothiazines, some H1 receptor antagonists); Physostigmine (counteracts antimuscarinic CNS effects) TX OF ALZHEIMER'S: Donazepil/Aricept |
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T/F: sx of AChE inhibitor intoxication will/can include Muscarinic, Nicotinic and CNS sx.
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TRUE
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What are the Muscarinic sx of AChE inhibitor toxicity?
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SLUDGE-BAM
S-salivation, sweating L-Larcrimation (tearing) U-Urination D-Defecation G-GI cramps E-Emesis B-Bronchoconstriction & bradycardia. A-Accomodation (spasm) M- Miosis or Muscle-twitches/fatigue - nicotinic) |
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What are the NMJ Nicotinic effects of intoxication with AChE inhibitor?
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Fasiculations--->Fatigue --->Weakness--->Twitches--->Paralysis
This is a cholinergic crisis. With Paralysis you can have paralysis of the diaphragm. |
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What are the CNS effects of intoxication with AChE inhibitor?
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First: confusion, ataxia, slurred speech, lost reflexes
Then: convulsions, coma and respiratory paralysis |
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What is the ultimate end result if intoxication with AChE inhibitor is not recognized and treated?
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Death from resp failure w/ secondary CV problems.
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What is the tx for AChE inhibitor intoxication?
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Atropine to reverse muscarinic sx. (can cross the BBB)
Supportive: remove source of exposure, support respirations/ventilations, treat any convulsions, treat for shock. Pralidoxime: give ONLY if person exposed to organophosphate inhibitor. |
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What is a significant delayed sequelae to organophosphate AChE inhibitor exposure?
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Ginger Jake Syndrome of delayed neuropathy.
Demylination of peripheral neurons....can lead to paralysis particularly in LEs. Starts at fingers and toes an works inward. |
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T/F: Muscarinic ANTagonists cannot be overcome once they are at the M receptor.
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FALSE - Muscarinic antagonists are competitive antagonists and can be overcome with sufficient ACh.
(And remember that as antagonists they have no intrinsic activity at the receptor...only block it. ) |
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T/F: All muscarinic responses to muscarinic antagonists are equally sensitive.
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FALSE: decreases in sweat gland, salivary gland and bronchial secretions occur at lower doses of muscarinic antagonists than decreases in GI motility and gastric secretions.
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What are the natural muscarinic antagonists (belladonna alkaloids)?
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Atropine sulfate/Belladonna: very specific M antagonist.
Scopolamine: muscarinic antagonist; more CNS effects than atropine |
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What are the synthetic muscarinic antagonists?
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Ipratroprium Bromide/Atrovent: inhalant asthma tx.
Glycopyrolate (robinul): quarternary amine compounds. |
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What are the 3 classes of AChE inhibitors?
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Overall, AChE inhibitors prevent AChE from hydrolizing ACh, making more ACh available to bind at receptor site & exert chlinergic effects.
REVERSIBLE INHIBITORS: Not actually hydrolyzed, but binds to & blocks the anionic site on AChE which blocks Ach from the esteratic site….briefly. SLOWLY REVERSIBLE/ Carbamate inhibitors: Forms carbamylated intermediate. Ach hydrolysis proceeds, just more slowly. IRREVERSIBLE/ Organophospate inhibitors: No charge, so crosses BBB. Rapidly interacts with AChE esteratic site & forms a very stable phosphorylated enzyme intermediate. Dephosphorylation occurs so slowly or not at all. |
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What is Pralidoxime (2PAM)?
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A cholinesterase reactivator; dephosphorylates active center of AChE.
Give only for organophosphate exposure before "Aging" of agent occurs. |
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T/F: AChE inhibitors block AChE at all sites?
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TRUE
At postgang PNS sites they exert parasympathomimetic effects: GI/GU - increased tone/motility, EYE - miosis, decreased ocular pressure, GLANDS - increased secretions Nicotinic sites: ANS ganglia get excitation then depol block (so inhibited activity); NMJ of SkMuscle get muscle contraction then depol block. CNS: activation then depr at ↑ doses. Increase sweat gland secretion. CV: complex effects s/t activation at pregang & postgang ANS sites. |
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What are the 6 main Therapeutic Uses of AChE inhibitors?
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TX of GLAUCOMA: Echothiopate (organophosphate AChEi) & Physostigmine (Carbamate AChEi)
GI/URINARY: tx atony of GI tract & urinary bladder smooth muscle. NOT if obstructed, peritonitis or gut viability ???. TX of MYASTHENIA GRAVIS: AChE inhibitors increase amt of ACh in cleft to outcompete antibodies are receptor site. DoC: Neostigmine REVERSAL OF NMDB BLOCKADE TX of MUSCARINIC ANTAGONIST INTOXICATION: give AChE inhibitor so ACh available to outcompete the musc antagonist. TX of ALZHEIMER'S: Increases amt of ACh in cleft. Donazepil/Aricept. |
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What are the drawbacks of Echothiopate?
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High risk of developing cataracts. Last resort med.
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If a person has GI atony s/t biteral vagotomy, would you use a AChE inhibitor or a muscarinic agonist? WHY?
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A muscarinic agonist. B/C s/t to the Bilat vagotomy, there is NO ACh released at the receptor site. So no matter how much you inhibit thet AChE there, there is no endogenous NT to form the DR complex and elicit peristalsis.
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What class of drug and what specific drug is used for differential dx between myasthenia gravis and cholinergic crisis?
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AChE inhibitor; Edrophonium (↑ ACh in cleft).
Give a dose: If strength improves, then the patient has myasth gravis. If pt get weaker, they have a cholinergic crisis (already in depol block, just flood the receptors more) |
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A pt getting and AChE for tx of a condition like myasthenia gravis can have some unpleasant muscarinic SE. Is it wise to give a muscarinic antagonist to balance/dampen these SE? Why?
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No, b/c the pt gets tolerant to the SE and a muscarinic antagonist can mask sx of AChE inhibitor toxicity.
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Name some other drugs that can exert a muscarinic antagonist effect?
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Atropine (duh), tricyclics, phenothiazines (antipsychotics), some H1 receptor antagonists
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What are the s/sx of cholinesterase inhibitor toxicity?
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Muscarinic Sx:
S - Salivation/Sweating L - Lacrimation U - Urination D - Defecation G - Gastric Cramps E - Emesis B - Bronchoconstriction/Bradycardia A - Accomodation M - Miosis (Muscle twitches/fatigue) Nicotinic: fatigue, weakness, twitches, paralysis after fasciculaton and onset of depol block. CNS: confusion, ataxia, sluured speech, lost reflexes, convulsions, coma, central resp paralysis DEATH: s/t resp faily w/ CV problems |
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What is tx of Cholinesterase Inhibitor Toxicity?
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Atropine - for muscarinic effects
Supportive measures: remove exposure source, respiration/ventilation, treat convulsions, tx for shock. |
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If a person presents with sx of cholinergic crisis/AChE inhibitor toxicity, would you consider Prilodoxime as a tx?
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ONLY if you could ascertain patient had been exposed to an organophosphate.
If they have not been exposed to an organophosphate, they are likely in depol block, which cannot be reversed...only waited out. |
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You could counsel a pt that they may experience sx of "Delayed Neuroxicity" after exposure to which AChEi: Malathion, Carbaryl, Sarin or Edrophonium
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Edrophonium is an reversible AChEi. Not an organophosphate (which has Delayed Neurotoxicity as sequelae to exposure). No.
Malathion is an organophosphate, but is biotransformed by carboxyl esterases, which mammal & birds have plenty of. No. Carbarly (Sevin dust): it is a Carbamate inhibitor & does not cause Delayed Neurotoxicity. No. Sarin is an irreversible organophosphate and is a known Nerve Agent. It causes Delayed Neurotoxicity. Sarin is the answer. |
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What is the five line mnemonic to help one remember sx of Muscarinic Antagonist Toxicity?
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Hot as a Hare (block of SNS cholinergic receptors---> no sweating).
Blind as a Bat (Midriasis, paralyzed accomodation s/t M blockade at eye sphincter and ciliary muscle) Dry as a Bone (s/t blockade of M receptors at salivary and sweat glands) Red as a Beet ("atropine flush") Mad as a Hatter (CNS effects: blockaded release of ACh in brain; impaired cognition, excitement, hall, restlessness) |
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What are some other drugs that have antimuscarinic SE?
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Tricyclics
Phenothiazines (antipsychotics) H1-receptor agonists |
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If an elderly person is showing acute sx of dementia, what may you want to check?
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Check home meds for ANTI-MUSCARINICS: Elderly and children are more vulnerable to antimucarinics and their CNS effects can mimic dementia.
Some OTC cold remedies have drugs with antimuscarinic effects and the elderly (& children) are vulnerable to toxic effects. Also, tricyclic antidepressants, phenothiazines, and H1 antagonists have antimuscarinic effects. So, BEFORE you give them Aricept...d/c the cold medicine, etc and see if it gets better. |
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Tx for muscarinist antagonist OD?
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AChE inhibitor - Physostigmine (controversial): CNS effects reverse those of Muscarinic Antagonist
Diazepam for convulsions Support respirations, treat fever. |
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T/F: Nicotinic antagonists block all autonomic reflexes.
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TRUE - they block adrenergic control of arterioles (vasodilation, ↓BP, postural hotn) & block PNS control of GI/GU tract (↓tone, constipation & urinary retention), eye (cycloplegia, mydriasis) & glands (↓secretion) & ↓sweat gland activity.
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Admin of antimuscarinic and a nicotinic selective ganglion blocker/antagonist produce similar sx. How can you differentiate?
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They both look the same, but the nicotinic antagonist (selective ganglionic blocker) will not produce CNS effects.
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T/F: Nicotinic antagonists block all autonomic reflexes.
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TRUE - they block adrenergic control of arterioles (vasodilation, ↓BP, postural hotn) & block PNS control of GI/GU tract (↓tone, constipation & urinary retention), eye (cycloplegia, mydriasis) & glands (↓secretion) & ↓sweat gland activity.
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Admin of antimuscarinic and a nicotinic selective ganglion blocker/antagonist produce similar sx. How can you differentiate?
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They both look the same, but the nicotinic antagonist (selective ganglionic blocker) will not produce CNS effects.
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What are the 2 main types of Nicotinic Antagonist Neuromuscular blockers?
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Competitive/Nondepolarizing blockers.
Depolarizing blockers. |
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Compare the mechanism of action of depolarizing and ndNMB drugs.
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Depolarizing nicotinic antagonist (SUX) has 2 ACh molecules that bind to both alpha subunits on the N receptor to produce activity. The membrane depol is sustained in Phase 1 blockade; which cannot be reversed by ↑ ACh levels (AChEi will enhance depol NM blockadeers). Fasciculations prior to paralysis.
ndNMBDs competitively antagonize the actions of ACh at NM nicotinic receptors. Cause flaccid paralysis w/o fasciculations. Only 1 alpha subunit on receptor has to be occupied. |
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What is the "prototype" competitive/ndNMB drugs?
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d-Tubocurarine (curarre)
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Will long-acting nicotinic antagonist, competitive/ ndNMB drugs cross the BBB?
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No
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All the drugs we think of as non-depolarizing NMBDs belong to what class of drugs?
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Nicotinic Antagonists
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If you needed a long-acting ndNMBD and needed to ↑ HR and MAP, would you choose Pavulon or curare?
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Pancuronium (Pavulon)
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T/F: Phase 1 blockade can be reversed by increasing amt of ACh in cleft?
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FALSE: Phase 1 blockade (the depol blockade by a depolarizing NMBD) cannot be reversed by increased ACh at site...already has excess agonist
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Sux is hydrolyzed by what?
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pseudocholinesterase.
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What are some SE of Sux admin?
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hyperkalemia
↑ intraocular pressure, ↑intragastric pressure. Cardiac dysrhythmias |
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If a patient has a prolonged time waking after admin of Sux, the anesthetist should suspect what?
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Pseudocholinesterase defeciency.
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Describe the Dibucaine # values and their meanings.
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80: Homozygous typical, sux lasts 5 minutes.
40-60: Heterozygous, sux modestly prolonged 20: Homozygous Atypical, sux greatly prolonged. |
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What can mimic pseudocholinesterase deficiency in a patient receiving sux?
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An ChE inhibitor that blocks pseudocholinesterase
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Review the suffixes of drugs we have in this section so far and ID their class...
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-curonium: aminosteroid
-curium: intermediate ndNMBD -stigmine: ChE inhibitor -choline: cholinergic. |
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What are some SE of Sux?
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HyperK+, ↑ intraocular pr, ↑ intragastric pr., cardia dysrythmias s/t stim of cardiac M receptors.
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Will NMBDs have analgesic or amnestic effects?
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No, b/c they do not cross the BBB.
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What are the causes of CV effects of NMBDs?
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combo of effects at autonomic ganglia (they are nicotinic antagonists), at cardiac muscarinic receptors & s/t histamine release.
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What NMBDs cause histamine release?
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Sux (slight), atracurium (slight), mivacurium (modest), d-Tubocurarine (moderate)
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What NMBDs effect cardiac muscarinic receptors?
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Pancuronium - modest block (↑HR)
Sux - modest stimulation (bradycardia) |
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What NMBDs effect nicotinic ganglionic receptors?
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d-Tubocurarine - moderate block
Sux - modest stim. |
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T/F: adequate blockade by a NMBD can provide adequate anesthesia.
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FALSE: NMBDs have NO analgesic or amnestic effects; d/t their paralytic effects they can reduce the amt of GA required.
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What are some practical uses of NMBDs?
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Facilitate tracheal intubation
Provide relaxation for optimal surgical working conditions. Muscle relaxation for ortho procedures. Decrease of muscular reaction to ECT. |
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What other drugs ENHANCE effects of ndNMBDs?
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LAs
Inhalant anesthetics Antibiotics: Aminoglycosides, tetracycline |
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What are the sx of a NMBD overdose? tx?
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Sx: prolonged apnea, histamine release, CV collapse
Tx: Support respirations, ChE inhibitor + atropine for ndMNBD |
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If you are going to use a NMBD for a patient with a hx of asthma, what may guide your choice of drugs?
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You'd want to choose a NMBD that did not cause histamine release
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If you were preparing to intubate a patient with 2nd and 3rd degree burns over 45% of their BSA, what consideration would you make in choosing their induction meds?
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These patients will likely have excess receptors at the skeletal NM jx site...giving sux could cause a hyperkalemic response.
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MH is due to what?
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a genetic problem with the ryanodine receptor which causes massive Ca++ release s/t lack of resequestration into SR. This leads to muscle rigidity with quickly uses IC stores of energy -->lactic acidosis.
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What does Dantrolene do?
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Uncouples Ca++ release from SR resulting in decreased muscle rigidity and decreased lactic acidosis.
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Muscarinic Receptors are found in what locations?
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Post ganglionic PNS
Sweat Glands (SNS) Blood Vessels (only the ones on the penis work) CNS |
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Side Effects of Muscarinic Agonists require precaution in what patients?
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ASTHMA (bronchoconstriction!!)
HYPERTYROIDISM (upregulation of beta adrenergic receptors requires PNS tone) CORONARY INSUFFICIENCY (will decrease efficiency of heart due to decreased cardiac tone) PEPTIC ULCER (will increase gastric secretions) OBSTRUCTION PRESENT (urinary tract) GI or URINARY TRACT INTEGRITY questionable |
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What is the difference b/n Achesterase Inhibitors that are Drugs and those that are insecticides and toxins?
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AchEsterase Inhibitor DRUGS: act primarily on the target organs (M Receptors). The ganglia are covered with connective tissue so nicotinic effects are not seen as much.
TOXINS: you see more nicotinic effects. |
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How does AChE work?
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It has an anionic site and an esteratic site. The anionic site attracts the positively charged quaternary ammonium compound. This attraction brings it close so that the esteratic site can cleave the ester bond of the ACh. The acetate grp is left. This creates an intermediate enzyme form that is know as “acetylated” . The enzyme hates this. It does not like being acetylated. It immediately spits the acetate grp out. …regenerating the enzyme…this is why it works so rapidly.
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Explain myasthenia gravis
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Autoimmune response where your immune system attacks the nicotinic receptors at the NM Junction. This decreases the # of nicotinic receptors and Leads to weakness and paralysis.
Dx with Edrophonium Tx with Neostigmine. |
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Precautions to take with Adrenergic Agonist Drugs...
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* Hyperthyroidism: (upregulation of beta adrenergic receptors so have a hyperSNS tone). Arrythmias can occur.
*Severe hypertension (adrenergic agonists will increase BP even more) *Heart disease (will directly stimulate the heart and generally will make it less efficient..not good…want to slow it down not speed it up.) *Angina *Congestive heart failure: increases HR but makes heart less efficient *Halogenated hydrocarbons (halothane): Sensitize heart to sympathomimetics and can cause cardiac arrhythmias (SVT), HTN, etc |
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Side Effects of Adrenergic Agonists
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*Increased BP: headache, palpitations, cerebral hemorrhage or pulmonary edema
*Increased cardiac workload: angina or myocardial infarction (especially B1 agonists) *cardiac arrhythmias (B1) *CNS stimulation *Norepinephrine: marked ischemia and necrosis with subcutaneous application (a1). Can occur during intravenous administrations. Can be reversed with an alpha antagonist. |
