Cell Physiology & Muscle Relaxants Flashcards
What is the most abundant component of the cell membrane on the basis of # of molecules?
Phospholipids
What is the most abundant component of the cell membrane on the basis of weight?
Proteins
Nonpolar Molecules
Nonpolar: Uniformly distributed charge NO net charge Lipophilic/hydrophobic Ex: O2, N2, inhalational/IV agents
Polar Molecules
Polar: Clustered charge \+/- poles repelled by lipid bilayer NO net charge Hydrophilic/lipophobic Ex: glucose, H2O, CO2
Who crosses the lipid bilayer?
Hydrophobic: O2, N2, IV anesthetics, inhalational agents
Small Polar: H20, CO2, urea, glycerol
Who can’t cross the lipid bilayer?
Large Polar: glucose, sucrose
Ions!
2 Types of Endocytosis
- Pinocytosis aka cell drinking - NO digestion (how proteins are reabsorbed from the PCT of the kidney)
- Phagocytosis (how macrophages eat bacteria)
Describe the type of receptor at the NMJ.
Ligand gated channels
Ach binds to nicotinic receptor, channel opens - Na + Ca diffuse IN, K diffuse OUT
Receptors are found on the outside surface of the lipid bilayer. Enzymes are found on the inside surface of the lipid bilayer. What is the exception?
At the NMJ, acetylcholinesterase projects outward into the synaptic cleft
A membrane receptor either operates a _________ OR controls an __________.
Receptor
Enzyme
What proteins are the best known for relaying messages from receptors to enzymes?
G proteins
What is the result of increased cAMP in the heart?
In the lung?
Heart - increased contractility (increased Ca) - Beta 1 agonists
Lung - bronchodilation (decreased Ca) - Beta 2 agonists
Na-K Pump
3 Na OUT
2 K IN
Insulin stimulates the _________ and opens ________ channels.
Na-K pump
Glucose
What 2 things stimulate the Na-K pump?
- Insulin
2. Beta 2 agonists (Ritodrine, Terbutaline)
Examples of 2nd messengers.
cAMP cGMP IP3 Calcium Calmodulin
Intracellular vs. Extracellular Ionic Gradients
Intracellular: K, PO4, Mg
Extracellular: Na, Cl, HCO3, Cl
In the resting cell, what lines the outside membrane? Is it positive or negative? What lines the inside membrane? Is it positive or negative?
Outside - K - positive charge
Inside - proteins - negative charge
What is the resting membrane potential? This is mostly determined by________.
70 mV
K
What happens to the resting membrane potential in the presence of hyperkalemia?
Decreased diffusion gradient through the leak K channels
Decreased K leaving the cell
RMP changes from -70 to -60
Cells depolarize
What happens to the resting membrane potential in the presence of hypokalemia?
Increased diffusion gradient through the leak K channels
Increased K leaving the cell
RMP changes from -70 to -80
Cells hyperpolarize
Describe the 4 stages of action potentials.
- Resting: (- 70 mV)
- Depolarization: Na channel opens, Na moves IN, (+ 30 mV)
- Repolarization: Na channel now in inactivated state, K channel opens, K moves OUT
- Restore Ionic Balance: the job of the Na-K pump
When is the absolute refractory period?
When the Na channel is in the inactivated state
Name 3 examples of the absolute refractory period…when the Na channel is in the inactivated state
- Cardioplegia
- Sux
- LA
In the neuron, where are the Na channels found?
On the axon
Diffusion of ____ ions INTO the cell is responsible for depolarization of the axon.
Na
Diffusion of _____ ions OUT of the cell is responsible for repolarization of the axon.
K
What is found embedded in the lipid bilayer of the presynaptic nerve terminal?
Nicotinic receptor (increases synthesis and release of Ach, this is a positive feedback loop)
Ca channel (Ca IN, NT OUT)
What is found postsynaptically in the membrane of the motor end-plate?
Nicotinic receptor
Acetylcholinesterase
What happens when BOTH alpha subunits of the nicotinic receptor are occupied by Ach?
Channel opens
Na + Ca diffuse INTO cell
K diffuse OUT of cell
Depolarization
Describe the termination of Ach.
Acetylcholinesterase aka “True” cholinesterase
Ach is broken down into choline (recycled) and acetate
What is associated with a DECREASE in the amount of NT released?
Decreased calcium
Increased magnesium
What is associated with an INCREASE in the amount of NT released?
Increased calcium
Decreased magnesium
How many Ach molecules are needed to open each nicotinic receptor?
2
40K, alpha subunits
How do NDMR work?
Competitive inhibitors
Inhibit Ach from attaching to the 2 alpha subunits of the nicotinic receptor
Channel remains closed
How does Sux work?
Sux mimics Ach
Opens the channel by binding to the nicotinic receptor
Channel stays open
Na channels remain in the inactivated state
Sux is composed of 2 ______ molecules.
Ach
How is Sux metabolized?
Plasma cholinesterase/Pseudocholinesterase
As metabolized, gradient develops - Sux diffuses away from the motor end-plate
The nicotinic receptor found presynaptically increases the synthesis and release of Ach - positive feedback.
Does Sux do this?
Yes - presynaptic action of Sux enhances its postsynaptic action
Augments the release of Ach
MR: Short DOA
Sux
Mivacurium
MR: Intermediate DOA
Atracurium
Cisatracurium
Vecuronium
Rocuronium
MR: Long DOA
d-Tubocurarine Metocurine Pancuronium Gallamine Pipecuronium Doxacurium
Structure of Quaternary Ammonium Compounds
Nitrogen surrounded by 3CH3 and 1CH2-R
Are MR ionized? Protein bound? Do they cross the BBB/placenta?
Yes - 100% ionized at physiologic pH
Yes - very protein bound
NO - do NOT cross the BBB/placenta
What 2 MR are eliminated primarily by biliary excretion?
- Vec
2. Roc
What 4 MR are eliminated primarily by metabolism?
- Sux - plasma cholinesterase
- Mivacurium - plasma cholinesterase
- Atracurium - Ester hydrolysis (nonspecific esterases) + Hofmann
- Cisatracurium - Hofmann
All other MR are primarily eliminated by…
Renal excretion
*All MRs can be excreted by the kidney (trapped d/t ionization)
Hofmann elimination depends on what…
pH
Temp
Increase rate with increase in pH + increase in temp
What MR stimulates the autonomic ganglia?
Sux
What 2 MRs produce autonomic ganglionic blockade?
- d-Tubocurarine - mod
- Metocurine - mild
* Block nicotinic receptors at the autonomic ganglia
What 2 MRs are vagolytic or have an antimuscarinic effect?
- Pancuronium
2. Gallamine
What MR causes bradycardia?
Sux
*Directly stimulates muscarinic receptors of the SA node
What 3 MRs lead to decreased BP?
- Sux
- d-Tubocurarine
- Metocurine
What 2 MRs lead to increased BP?
- Pancuonium - mild
2. Gallamine - mod
Which MR can increase HR in children but not in adults?
Roc
Name 5 MRs that release histamine.
- Sux
- Mivacurium
- Atracurium
- d-Tubocurarine
- Metocurine
Name 5 MRs that cause tachycardia.
- Atracurium - reflex
- d-Tubocurarine - reflex
- Metocurine - reflex
- Pancuronium - mod
- Gallamine - marked
Name adverse effects of Sux.
Increased IOP, ICP, IGP Hyperkalemia (normal 0.5 mEq/L, burn/trauma/HI 5-10 mEq/L) Bradycardia, AV block Mus pain - fasiculations Myoglobinuria Atypical plasma cholinesterase MH
What makes Sux-induced hyperkalemia worse?
Proliferation of extrajunctional post-synaptic cholinergic nicotinic receptors…up regulation
Nicotinic receptor sitmulation - channel opens - K exits
BURNS, PARA/HEMIPLEGIA, TRAUMA, UMN INJURY
(HI, CVA, Parkinson’s), MUSCULAR DYSTROPHY
The patient has right sided hemiplegia…twitch monitor should be placed on the right or the left?
Left
Right will be exaggerated (upregulation)
Malignant Hyperthermia
Sarcoplasmic reticulum fails to sequester Ca - sustained contraction - increased metabolism - hypercarbia
Increased ETCO2 = earliest, most sensitive
SNS stimulation - increased HR, RR
Trismus 50%, whole body rigidity 75%
Increased: H, K, Ca, CO2
Decreased: O2, pH
Tx: d/c causative agents, hyperventilate, Dantrolene, cool, treat hyperK
What are the 2 agents that trigger MH?
- Sux
2. Volatile inhalational agents
What increases the block of NDMR?
Abx (mycin), LA, volatile agent, HYPOkalemia, HYPERmag, acidosis, HYPOthermia, increased age, lithium, diuretics, CCB, antiarrhythmias, renal disease, hepatic disease, MG
What decreases the block of NDMR?
- Anticonvulsants
2. Burn injury
What increases the block of Sux?
Abx (mycin), LA (ester), anticholinesterase agents, HYPERkalemia, HYPERmag, lithium, CCB
What increase the block of NDMR, but does NOT affect the block of Sux?
Volatile agent
At this % of receptors blocked you have no twitches in TOF BUT the diaphragm moves?
95%
This % of receptors blocked is adequate for intra-abdominal procedures?
1/4 twitches
90%
TV returns to normal when what % of receptors are blocked?
75-80%
*Not an indicator of recovery
What % of receptors are blocked when you have no palpable fade in TOF? And you have sustained tetanus 50 Hz for 5 seconds?
70-75%
What % of receptors are blocked when you have no palpable fade in DBS?
60-70%
What % of receptors are blocked with head lift for 5 sec, sustained handgrip, and sustained bite?
50%
What % of receptors should be blocked for intubation?
> 95%
When monitoring Sux on a peripheral nerve stimulator know that…
Twitches will be reduced in amplitude
NO fade in TOF, DBS, or tetany
NO post-tetanic facilitation
*Block is antagonized by NDMR
Define phase I block.
Motor end-plate is depolarized
Ion channels are open
Define phase II block aka desensitization.
Result of increased doses of Sux or prolonged exposure
Ion channels close, motor end plate repolarizes
Looks like a NDMR block on a peripheral nerve stimulator
Name the enzyme that breaks down cAMP to 5’AMP.
Phosphodiesterase
Describe the pathway of nitric oxide, starting with the amino acid that is the immediate precursor of nitric oxide.
L-arginine - NOS - nitric oxide - guanylate cyclase - cGMP - PKG - decrease Ca in cytoplasm
What is the name of the specific type of enzyme-linked insulin receptor?
Tyrosine kinase receptor
What is the most common excitatory NT in the CNS?
Glutamate
Name 6 ligand binding sites of the GABA receptor.
- GABA
- Barbiturates
- Benzos
- Propofol
- Steroids
- Anesthetics/alcohol
How fast does temp increase with MH?
1-2 deg C Q5 min
Dantrolene
Works of what receptor?
What is the dose?
What does a vial of Dantrolene contain?
Ryanodine receptor
2.5 mg/kg Q 5min Max 10-20 mg/kg
20 mg of Dantrolene + 3 G of Mannitol - mix with 50 mL of sterile water
What is the best method for decreasing temp in the case of MH?
Gastric lavage
STOP cooling at 38 deg C
What syndrome can mimmic MH?
Neuroleptic malignant syndrome (NMS) - antipsychotic agents, dopamine depletion
MH has an acute onset, NMS develops over 24-72 hrs
Duchenne’s Muscular Dystrophy
Males or females?
Diagnosis at the age of?
Concerns?
X-linked recessive disorder - affecting males
Diagnosed at 3-5 years
Concerns - Myocardial dysfunction, hyperK with Sux, MH
Myasthenia Gravis Cause? Most common onset? Tx? Major concern?
Autoimmune destruction of nicotinic receptors at the NMJ
Ocular - ptosis and diplopia
Tx: anticholinesterase drugs
Major concern - postop respiratory failure
*Sensitive to NDMR and sensitive or resistant to Sux
Cholinergic Crisis S/S? Drugs that could be possible causes? Diagnosis? Tx?
Accumulation of Ach
Excessive muscarinic receptor stimulation - weakness, diarrhea, salivation, miosis, bradycardia
Anticholinesterase drugs, organophosphates, insecticides, pesticides
Diagnosis - give edrophonium- if they get better then it is a myasthenic crisis - if they get worse then cholinergic crisis
Tx? Atropine + Pralidoxime (reactivates acetylcholinesterase)
Lambert-Eaton Myasthenic Syndrome Cause? S/S? Associated with? Does weakness improve with repeated stimulation?
Antibodies attack Ca channel
Proximal skeletal mus weakness that typically affects the LE
Associated with small-cell carcinoma of the lung
Yes - weakness improves with repeated stimulation
*Sensitive to both NDMR and Sux
Does Sux have an active metabolite?
Yes - succinylmonocholine
Sux is contraindicated for patients taking what eye drop medication?
Echothiophate
Benzylisoquinolines
NDMR with “curium”
*Steroid derivatives have “curONium”
Name the metabolite of ester hydrolysis of Atracurium.
Laudanosine - CNS stimulant
Which 3 MRs have active metabolites?
- Sux
- Vec
- Pancuronium
How does a pretreatment dose of NDMR affect Sux?
Sux is less potent and has a shorter DOA
What happens to the potency of a NDMR given after Sux?
Potency is enhanced
Name 4 anticholinergic/antimuscarinic drugs.
- Atropine
- Glyco
- Scopolamine
- Ipratropium
Which antimuscarinic has the greatest…
antisialagogue effect?
sedative and amnesic effect?
heart rate effect?
Scopolamine
Scopolamine
Atropine
How do antimuscarinics interfere with sweating?
Large doses of atropine increase body temp by preventing sweating
Sweat glands contain antimuscarinic receptors (Ach is released by sympathetic postganglionic neurons)
Antimuscarinics have what effect on the lower esophageal sphincter?
Decrease the tone of the lower esophageal sphincter
Anticholinergic Syndrome
What 2 drugs are responsible?
Central and peripheral S/S?
Tx?
- Scopolamine
- Atropine
S/S: Confusion to coma, BUDCAT
Tx: Physostigmine
What would you consider if your patient with myasthenia gravis exhibits excessive salivation?
Muscarinic side effects
Excessive anticholinesterase drug effects
If muscle weakness, consider cholinergic crisis
What 3 drugs should be avoided in a patient with atypical pseudocholinesterase?
- Sux
- Mivacurium
- Ester-type local anesthetics
Describe the dibucaine test.
What is normal?
Dibucaine depresses the activity of pseudocholinesterase
Normal - dibucaine will depress the activity of pseudocholinesterase by 70-85% - 70-85
Heterozygotes - 30-70
Homozygotes - 20
*The dibucaine # does NOT reflect the quantity or concentration of the enzyme
List the 4 anticholinesterase agents/cholinesterase inhibitors.
- Edrophonium - quaternary amine (charged)
- Neostigmine - quaternary amine (charged)
- Pyridostigmine - quaternary amine (charged)
- Physostigmine - tertiary amine (uncharged) - crosses the BBB
