Nicotine is medically significant because of....
- presence in tobacco products
- eliciting increased cardiac rate, vasoconstriction, and plasma levels of epinephrine; decreased mucociliary movement in lungs; mildly stimulates CNS
- addictive properties
- small cell carcinoma of the lung
- cardiovascular disease
- difficult to determine which chemicals are responsible for toxic effects of tobacco consumption (nicotine, aldehydes, nitrosamines, other alkylating agents)
Chronic nicotine toxicity is characterized as the largest single preventable cause of illness and premature death in the U.S.
What is a lethal dose for acute nicotine toxicity?
What population is this a concern for?
Ingestion of nicotine products by small children & dogs.
What dosages are in an average cigarette and cigar?
What are the symptoms of acute nicotine exposure?
Muscle endplate depolarization
What 4 out of the 5 major causes of death does nicotine contribute to?
Lung and other cancers
N2 receptor antagonists have limited clinical use due to their lack of selectivity.
N1 receptor antagonists because N1 receptors are found on all autonomic ganglia (both sympathetic and parasympathetic)
What symptoms does interruption of sympathetic ganglionic transmission result in?
Overall: inhibited cardiovascular reflexes and sweating
Vasodilation with increased peripheral blood flow to some vascular beds and decreased BP
- orthostatic hypotension
- decreased cardiac output
- decreased total peripheral resistance
Thermoregulatory and nonthermoregulatory sweating reduced
What 6 symptoms does interruption of parasympathetic ganglionic transmission result in?
Dry mouth (xerostomia)
Urinary retention and constipation
Mydriasis (dilated pupil)
Cycloplegia (loss of accommodation)
Impaired sexual function due to prevention of erection/ejaculation
Decreased GI tone/motility and secretions
1) What are the 2 ganglionic blocking agents?
2) What receptor are they affecting?
3) What effect do they have on the receptor?(non/depolarizing; non/competitive; ant/agonist)
1) mecamylamine & trimethaphan
3) nondepolarizing competitive antagonist
What effect does a high concentration of nicotine produce?
persistent depolarization of membranes in regions with N1 and N2 receptors
What 4 clinical problems can ganglionic blocking agents treat?
Hypertensive emergencies during surgery or following aortic aneurysm
Adjunct therapy for peripheral vascular resistance - relieve vasoconstriction and increase perfusion of tissue
Adjunct therapy for severe hypertension - not 1st choice therapy
Lowering arterial pressure to control bleeding during surgery
Take home: generally if an organ receives both parasympathetic and sympathetic innervation, the dominant tone will be parasympathetic. If an organ only receives sympathetic innervation, the dominant tone will be sympathetic.
What is the distribution of N2 receptors and AChE (acetyl cholinesterase) in the NMJ?
N2 receptors are localized at the end plate region at the center of the muscle fibers.
AChE is concentrated in the folds of the end plate region.
AChE inhibitors lead to what overall effect?
Increased concentration of ACh at NMJs, facilitating the ability to reach threshold level and generate a muscle action potential
What is denervation supersensitivity?
Loss of innervation thru trauma or a degenerative process leads to the threshold dose of ACh needed to trigger a response being significantly reduced.
-N2 receptors redistribute across the muscle surface
-Increased numbers of receptors are expressed across the muscle surface
What effect does denervation have on smooth muscle? Skeletal muscle?
Smooth muscle does not atrophy
Skeletal muscle atrophies
Both show supersensitivity
What are the clinical applications in the use of neuromuscular blocking agents?
Muscle relaxant and adjunct for anesthesia
- muscle relaxation for intracavitary surgery
- facilitate tracheal intubation
- control of ventilation in patients with ventilator failure
- treatment of convulsions
What are the concerns/considerations of administering a NM blocking agent?
-ensure adequate ventilation
-no bronchial airway obstruction
-no CO2 accumulation
-require proper training to support respiration and cardiovascular system
What are the 3 effects of nondepolarizing N2 receptor competitive inhibitors?
1) Block opening of Na channel
2) Unbound ACh is hydrolyzed by AChE at NMJ
3) Motor weakness -> total flaccid paralysis -small rapidly moving muscle function lost first -limb, neck, and trunk muscle function lost next -intercostal muscles and diaphragm function lost last
What are the 2 factors in selecting a nondepolarizing inhibitor?
-duration of drug action
-minimizing cardiovascular and other side effects (cross-reactivity with N1/M and histamine release)
What is the actual nicotine delivery through cigarette? Where does the rest go?
Actual drug delivery ~1-2.5mg with most nicotine lost thru burning or as 2nd hand smoke
What is another way of exposure to nicotine besides cigarettes & cigars?
Exposure to insecticides with nicotine as the active ingredient
What happens with re-innervation after denervation supersensitivity?
With re-innervation, denervation supersensitivity will disappear and cholinergic receptors will reestablish an organized end plate region.
Do the NM blocking agents posses tertiary or quaternary nitrogen(s)? What does this mean for solubility?
All NM blocking agents possess 1-2 quaternary nitrogen groups, resulting in poor lipid solubility and inability to cross BBB.
What would happen if neostigmine is used alongside a nondepolarizing N2 receptor competitive inhibitor?
Neostigmine is an AChE inhibitor and will elevate effective concentration of ACh at NMJ and allow ACh to compete off nondepolarizing agent.
What is the duration of drug action of d-tubocurarine (aka. curare) & pancuronium?
What is the duration of drug action of cisatracurium & vecuronium?
What chemical group are d-tubocurarine (aka. curare), vecuronium, and mivacurium in?
What are the effects of benzylisoquinolines (d-tubocurarine (aka. curare), vecuronium, and mivacurium)?
No vagolytic (M receptor cross-reactivity) or ganglionic blocking activity (N1 receptor cross-reactivity)
Elicit some histamine release
What chemical group are pancuronium, vecuronium, and rocuronium in?
What are the effects of ammonio steroids (pancuronium, vecuronium, and rocuronium)?
Virtually no histamine release
Some muscarinic block
Elicit vagal blockade and tachycardia (newer agents eliminate tachycardia)
What is a phase I NM block?
Membrane remains depolarized and unresponsive to later impulses; flaccid paralysis results due to lack of repolarization; ChE inhibitors augment block
What is a phase II NM block?
With prolonged exposure, membrane repolarizes but is resistant to further depolarization
Succinylcholine has what effect on what receptor?(non/depolarizing; non/competitive; ant/agonist)
Noncompetitive N2 receptor agonist, opening Na+ channels (ACh mimic)
What enzyme breaks succinylcholine down?
What does this mean for its half-life?
Plasma ChE rapidly hydrolyzes -> short half-life
*Not a substrate for AChE
What class are mecamylamine & trimethaphan in?
ganglionic blocking agents
Which describes succinylcholine's action? Phase I block or phase II block?
Phase I block (it is the only depolarizing NM blocker)
What are possible contraindications of nondepolarizing blockers?
- patients with liver &/or renal dysfunction will have an impaired ability to metabolize and excrete metabolic products
- some may induce hypotension by blocking ganglionic receptors or by releasing histamine from mast cells
- several antibiotics may potentiate neuromuscular blocking activity
- patients with myasthenia gravis already have decreased functional cholinergic interactions at skeletal muscle
What are the 4 possible contraindications for succinylcholine? Patients with...
1) Plasma ChE gene mutations - patients may exhibit prolonged neuromuscular blockade
2) Organophosphate intoxication - Plasma ChE in patients will be inhibited and thus succinylcholine activity will be potentiated if administered
3) Congestive heart failure, burns, trauma, or neuromuscular disease - excess K+ release into the blood during depolarization of skeletal muscle may result in cardiac arrest
4) Open anterior eye chamber due to injury - Depolarization of extraocular muscles can elicit rapid contraction resulting in increased intraocular pressure
What class of drugs are edrophonium and neostigmine in?
1) AChE inhibitors will readily reverse (antagonize) what effect?
2) What side effects are of concern?
3) What drug can be used in addition to limit these side effects?
1) Neuromuscular blockade produced by competitive blocking agents
2) Muscarinic and N1 receptors also affected -> hyperactivity of PS NS
What drugs can antagonize neuromuscular inhibition by succinylcholine?
What is the duration of action of edrophonium?
What is the duration of action of neostigmine?
1) What class are mecamylamine & trimethaphan in?
2) What effect do they have on the N1 receptor?(non/depolarizing; non/competitive; ant/agonist)
1) ganglionic blocking agents
2) nondepolarizing competitive antagonist