Montemayor CIS Flashcards
Tetrodotoxin (TTX)
No specific lab tests, dietary history is key for diagnosis
No proven antidote; activated charcoal binds toxin
MoA:
Blockage of Voltage-Gated Na+ Channels
What effect does blockage of voltage-gated Na+ channels have on action potential generation?
- Depolarization is inhibited
- AP generation/propagation is inhibited
Maintenance of the resting membrane potential is critical for excitable cells. Which change would most rapidly hypopolarize the RMP?
Blockage of K+ leak channels Decreased permeability of intracellular proteins Increased extracellular [Na+] Increased intracellular [Cl-] Inhibition of the Na+/K+ pump
repolarization phase is mainly due to voltage-gated channels
the leak channels are what maintain it.
Dendrotoxin blocks voltage-gated K+ channels, effectively inhibiting which phase?
the drop back down after action potential– the repolarization
What effect does dendrotoxin have on ACh release?
Inhibition of repolarization Prolonging AP Prolonged Ca2+ influx at nerve terminal Enhanced ACh release Hyperexcitability and convulsive symptoms
Anesthesia is induced with propofol and a neuromuscular blocking agent that produces muscle fasciculations upon administration. Which of the following fits this description?
Atracurium Neostigmine Rocuronium Succinylcholine Tubocurarine
Succinylcholine is a:
depolarizing neuromuscular blocker
acting on Ach receptors in muscle cell membrane
neostigmine is an AchE inhibitor, not a neuromuscular blocking agent
Neuromuscular Blocking Agents (NMBAs)
Two basic mechanisms:
Nondepolarizing blockade
Prevent access of ACh to its receptor and block depolarization
Prototype: tubocurarine
Depolarizing blockade
Neuromuscular blockade that results from excess of a depolarizing agonist
Prototype: succinylcholine is the only one avail. in the US
General anesthesia is maintained with sevoflurane while muscle relaxation is most likely maintained with which agent?
Donepezil Galantamine Mivacurium Succinylcholine Vecuronium
Answer: Vecuronium – nondepolarizing, intermediate acting
the wrong ones:
Donepezil – AChE
Galantamine – AChE
Mivacurium – nondepolarizing, short acting, histamine release
Succinylcholine – depolarizing, ultrashort acting
NMBAs: Clinical Indications
Surgical relaxation
Endotracheal intubation
Control of ventilation
Pharmacokinetics dictate choice of agent:
Rapid time of onset for rapid sequence intubation
Succinylcholine, rocuronium, vecuronium
Longer duration of action for surgical muscle relaxation
Pancuronium, atracurium, cisatracurium
Hepatic and/or renal insufficiency
Atracurium, cisatracurium
Acidosis starts to happen in the pt undergoing anesthesia and muscular blocking. At 4.5 hours after incision, the patient’s body temperature is 40.9C. At this time, a rise of more than 0.5 C is observed in less than 15 minutes. What is the most likely diagnosis?
Malignant hyperthermia
Malignant Hyperthermia
A rare, pharmacogenetic condition that can be triggered by volatile anesthetics & depolarizing muscle relaxants
- Anesthetics: halothane, isoflurane, sevoflurane, desflurane
- Depolarizing muscle relaxants: succinylcholine
Incidence: 1 in 15,000 children; 1 in 10,000-50,000 adults treated with anesthetics
Disorder of Ca2+ regulation in skeletal muscle
- Uncontrolled release of Ca2+ from the SR → rigidity, tachycardia, tachypnea, and hyperthermia
- Acute hyper-metabolic state within muscle tissue; prolonged contraction
- – ATP depletion leads to compromised muscle membrane integrity, causing hyperkalemia and rhabdomyolysis
- – Increased O2 consumption, increased CO2 production, acidosis
Typically rapid onset
Which receptor is most likely altered in MH?
About 50% of MH cases are caused by mutations in the RYR1 gene for the ryanodine receptor (Ca2+ - release channel)
- MH may also be linked to the DHPR (About 1% of cases)
Where is the ryanodine receptor (RyR) located?
- SR membrane
Where are Dihydropyridine Receptors (DHPR; L-type Ca2+ channels) located?
- T-tubule membrane
What is the role of the DHPR?
- Voltage sensor
What is the role of Ca2+ in the development of tension by skeletal m.?
TnC + Ca2+ removal of regulatory protein (Tropomyosin) from actin cross-bridge formation
Number of cross-bridges is directly proportional to tension production
What is required for muscle relaxation to occur?
Removal of Ca2+ from the sarcoplasm
Relaxation = Active process!
ATP is required:
- Ca2+ pumps
- ATPase binding site on myosin head (New ATP must be bound for cross-bridge to be broken)
What is the primary pump responsible for removing Ca2+ from the sarcoplasm in order for relaxation of skeletal muscle to occur?
- Sarcoplasmic and endoplasmic reticulum Ca2+- ATPase (SERCA)— type Ca2+ pump
Which of the following agents is most appropriate to treat the patient with malignant hyperthermia?
Cisatracurium Dantrolene Pralidoxime Pyridostigmine Rocuronium
Dantrolene
The only known pharmacologic treatment for malignant hyperthermia (other measures include cessation of triggering agent, ventilation with 100% O2, and surface cooling)
Also approved for management of spasticity associated with motor neuron disorders (multiple sclerosis, cerebral palsy, spinal cord injury, stroke)
MOA: directly binds to the skeletal muscle RyR1 and inhibits further Ca2+ release (antagonist)
If a patient presented with a family history of malignant hyperthermia, which neuromuscular blocker would be the most appropriate choice for endotracheal intubation?
Atracurium Pancuronium Rocuronium Succinylcholine Tubocurarine
Rocuronium
we were looking for a quick-acting choice
Aminoglycoside Toxicity
Nephrotoxicity, ototoxicity, and…
Neuromuscular blockade
Neuromuscular blockade is a rare but serious adverse effect induced by aminoglycoside therapy
Most patients experiencing such reactions have disease states and/or concomitant drug therapy that interferes with neuromuscular transmission
Use aminoglycosides with caution in patients with myasthenia gravis due to risk of respiratory failure or weakness
Myasthenia Gravis
Weakness and fatigue
- Worsen with increased activity, improve with rest
Neural conduction and sensory and autonomic responses are normal
Autoimmune: circulating antibodies directed against nAChR are commonly detected
Frequently: extraocular m.m. are initially affected (ptosis, diplopia, blurred vision) [small motor units]
- Bulbar muscles (speech and swallowing)
- Neck muscles
- Proximal limb muscles
Pt. with Myasthenia Gravis. For this patient, what effect does a normal presynaptic release of ACh have on the motor end plate? The end plate potential would be:
Decreased, likely not completely absent
Anti-nicotinic ACh antibodies
Immune-mediated destruction or impaired binding of nicotinic ACh receptors
Fewer channels capable of opening in response to ACh: ↓ ability to generate an end-plate potential
In skeletal muscle, ACh binding to nicotinic ACh receptors at the motor end plate directly results in opening of:
A. ligand-gated cation channels, & hyperpolarization of end plate to a Vm between the Na+ and K+ Eq.
B. ligand-gated cation channels, & depolarization of end plate to a Vm between the Na+ and K+ Eq.
C. voltage-gated Ca2+ channels, & depolarization of end plate to threshold potential.
D. voltage-gated K+ channels, & repolarization of end plate to resting potential.
E. voltage-gated Na+ channels, & depolarization of end plate to threshold potential.
B. ligand-gated cation channels, & depolarization of end plate to a Vm between the Na+ and K+ Eq.
nACh Receptor
Opening of nAChR channel at the motor end plate –> EPP
Permeable to cations
Function to raise Vm toward threshold
Na+ and K+ become equally permeable
Result: * relative increase in Na+ permeability vs. resting
- Vm shifts to a value between EK (−80 mV) and ENa (+50 mV)
What effect does the generation of an EPP normally have on the adjacent sarcolemma of a skeletal m. fiber?
Threshold reached –> voltage-gated Na+ channels open –> muscle Action Potential generated
What enzyme terminates neurotransmitter activity at the NMJ?
Acetylcholinesterase
Which enzyme catalyzes the synthesis of ACh?
Choline acetyltransferase:
Enzyme that synthesizes ACh from choline + acetyl coenzyme A
What drives ACh uptake into the vesicle?
Vesicular proton electrochemical gradient (positive voltage & low pH inside)
Neurotransmitter transport proteins:
ACh-H+ exchanger: ACh uptake by synaptic vesicle
(couples inward transport of ACh to H+ efflux)
What comorbid condition should you evaluate the myasthenia gravis patient for?
Graves’ disease Pernicious anemia Cushing syndrome Pheochromocytoma Thymoma
Thymoma
Often associated with tumors of thymic epithelial cells (thymoma)
30-45% of thymomas are detected in the course of evaluating patients with MG
Thymomas are associated with other autoimmune disorders
Hypogammaglobulinemia, Graves disease, pernicious anemia, Cushing syndrome
Administration of which agent is part of a test that may be utilized to support a diagnosis of myasthenia gravis?
Dantrolene Edrophonium Pralidoxime Succinylcholine Tacrine
Edrophonium
The patient has a positive response to an edrophonium (Tensilon) test. Her muscle weakness is improved by the acetylcholinesterase inhibitor (AChEI) due to increased:
A. ACh release at the presynaptic terminal
B. Binding affinity of ACh for nicotinic receptors
C. Ca2+ influx at the presynaptic terminal
D. Concentration of ACh in the synaptic cleft
E. Expression of nicotinic ACh receptors
Concentration of ACh in the synaptic cleft
Common tests for patients with suspected myasthenia gravis include the edrophonium (Tensilon) test, ice pack test, and blood test to look for nAChR antibodies
Why does the ice pack test produce temporary improvement for some patients?
Cooling slows or inhibits AChE activity
Myasthenia Gravis & the Eyes
90% of patients with MG develop ophthalmologic manifestations
2 major clinical forms::
- Ocular MG: strictly ocular symptoms
~15% had strictly ocular symptoms after 17yrs follow-up)
- General MG: generalized weakness
~85% of ocular MG patients progress to general within 2 yrs
Proposed reasons for impact on eyes:
Ocular weakness may be more noticeable in patients
Perhaps due to fewer ACh receptors in eye muscles (less prominent synaptic folds compared to limb muscles)
High rate of firing frequency of ocular motor neurons may contribute to neuromuscular transmission fatigue
Lower quantal release of ACh vesicles per synaptic event in ocular motor neurons
A past history of which condition in this patient would contraindicate administration of the Tensilon (edrophonium) test?
Asthma Gout Hypocalcemia Malignant hyperthermia Septicemia treated with gentamicin
Asthma- increased activation of muscarinic receptors
Which of the following agents would theoretically reduce symptoms of MG, but is not used in practice due to risk of hallucinations and seizures at high concentrations?
Azathioprine
Neostigmine
Physostigmine
Pyridostigmine
Physostigmine
Lipid-soluble and **uncharged AChE inhibitors (physostigmine, donepezil, rivastigmine, galantamine, tacrine) that cross the blood-brain barrier are inappropriate due to CNS adverse effects
- Subjective altering response at therapeutic concentrations
- Hyperstimulation of neurons, general convulsions, coma, respiratory arrest at toxic concentrations
Which of the following adverse effects is most likely with pyridostigmine?
Anhydrosis Cutaneous vasodilation Diarrhea Dry mouth Mydriasis
Diarrhea
Which of the following drugs may be used to reduce the patient’s symptoms of diarrhea?
Atropine Epinephrine Pyridoxine Pralidoxime Vecuronium
Atropine or glycopyrrolate
other choices that would work:
Dicyclomine, glycopyrrolate, hyoscyamine, ipratropium, tiotropium, oxybutynin, scopolamine, benztropine, etc.
Parasympathetic vs. Sympathetic Tone
Parasympathetic : Cholinergic Salivation, lacrimation Pupil constriction (myosis) Decrease in HR Increased secretion and motility Urination, defecation
Rest and digest
Smooth muscle contraction
Blocked by atropine
Sympathetic : Adrenergic (anticholinergic) Cutaneous vasodilation Pupil dilation (mydriasis) Increase in HR Decreased secretion and motility Reduction/elimination of the desire to urinate
Fight or flight
Smooth muscle relaxation
Reversed by acetylcholinesterase inhibitors
A 29 y/o male is brought to the emergency department unconscious, with nonreactive, pinpoint-sized pupils, massive oral foaming, and muscle fasciculations. Other than a 12 year history of depression, past medical history is unremarkable. Current medications include sertraline (Zoloft) and buproprion (Wellbutrin). He was recently prescribed varenicline for smoking cessation. He recently ate at a sushi restaurant. What is the most likely cause of his current presentation?
Cocaine intoxication Lambert-Eaton myasthenic syndrome Organophosphate exposure Tetrodotoxin intoxication Varenicline overdose
Organophosphate exposure
Which class(es) of drugs will address this patients organophospphate overdose symptoms?
Cholinesterase regenerator
Muscarinic acetylcholine receptor antagonist
Neuromuscular blocking agent
Nicotinic acetylcholine receptor antagonist
Peripherally acting spasmolytic
Cholinesterase regenerator
- pralidoxime
Muscarinic acetylcholine receptor antagonist
Can’t use nicotinic Ach receptor antagonist because of the risk of desensitization
A 43 y/o male with a history of small-cell lung carcinoma presents with proximal weakness and absent tendon reflexes. EMG initially shows a low-amplitude muscle response which significantly increases following repeated activation. Circulating antibodies directed against voltage-gated Ca2+ channels are detected.
Dx?
Lambert-Eaton Myasthenic Syndrome (LEMS)
Paraneoplastic syndrome
Is LEMS a pre- or post-synaptic disorder?
Pre-synaptic: autoimmune attack directed against voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal
Reduction in functional VGCCs
What is the role of Ca2+ influx in excitation of the neuromuscular junction?
Promotes ACh vesicle fusion and exocytosis
Which vesicle protein is considered to function as the Ca2+ sensor?
Synaptotagmin
Why does repetitive stimulation result in increased contractile strength in this patient with Lambert-Eaton vs. decreased strength after repetitive use in the patient with Myasthenia gravis?
Rapid, repetitive stimulation can increase Ca2+ influx via * functioning channels
Increase release of ACh
Presynaptic stores of ACh and postsynaptic AChR are intact –> the EPP will raise the membrane above threshold and permit generation of muscle AP
Treatment of LEMS
Evaluation for primary underlying malignancy
- Strong association with malignancy, especially small cell lung cancer
Symptomatic pharmacotherapy to increase ACh
- Guanidine
- Aminopyridines
- AChE inhibitors (especially pyridostigmine)
Immunologic therapies
- Intravenous immune globulin
- Glucocorticoids
Pt’s stool sample tested positive for Clostridium botulinum. She was diagnosed with botulism toxicity and quickly administered an antitoxin to limit any further damage.
Examination of this patient’s neuromuscular junction would reveal:
Decreased ACh receptor expression Decreased amplitude of postsynaptic APs Decreased synthesis of ACh vesicles Impaired ACh vesicle fusion Increased ACh receptor expression
Impaired ACh vesicle fusion (both botulinum and tetanus)
Administration of the botulinum antitoxin stabilizes the patient. Recovery will take weeks until which docking and fusion proteins are newly synthesized?
Synaptobrevin (v-SNARE) or SNAP-25 (t-SNARE)
A 10 y/o boy is brought to his primary care physician presenting with complaint of jaw pain, inability to fully open his mouth, difficulty swallowing, and generalized stiffness. His mother reports that his symptoms began in his jaw, but had worsened over the past couple of days since she first noticed he had been limping. His foot was swollen and tender where he had stepped on a piece of metal as he was walking barefoot in the backyard.
dx
Tetanus
The patient was taken to the ED where he received 500 units of human anti-tetanus immunoglobulin
Tetanus toxin binds irreversibly to tissues
Only unbound toxin is available for neutralization
Infection does not confer immunity upon recovery
Vaccination is indicated
Clostridium tetani vs. Clostridium botulinum:
Clostridium botulinum:
- peripheral effects
- flaccid paralysis
- inhibition of ACh release at the NMJ
With a similar molecular mechanism of action (effect on synaptobrevin), how do you explain the spastic paralysis resulting from tetanus toxin?
- Central effects
- – Binds NMJ presynaptic membrane, retroaxonally transported to SC
- NT release is blocked
- Impact spinal inhibitory interneurons
