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Know: Large water soluble (hydrophilic, lipophobic) molecules and ions do NOT diffuse through the lipid bilayer and therefore generally must use channels to enter and exit cells and cross the blood-brain and placental barriers.  Of all substances (including glucose), ions (Na+, K+, Cl-, etc.) are LEAST likely to penetrate lipid bilayers.
Question: Which molecules will pass through the lipid bilayer?
Hydrophobic molecules (including intravenous and inhalational anesthetics) and small, uncharged polar molecules (H20, C02) READILY PENETRATE the lipid bilayer.
Know the examples of endocytosis and exocytosis: proteins are reabsorbed from the proximal tubule of the kidney by PINOCYTOSIS; macrophages PHAGOCYTIZE bacteria; neurotransmitters are released from nerve terminals by the process of exocytosis.
2 types of endocytosis: pinocytosis (cell drinking) & phagocytosis (cell eating).
In exocytosis, an intracellular vesicle "melts" into the surface membrane before opening to the extracellular space and extruding its contents.
Chemicals that attach to the receptors of the cell membrane are called LIGANDS and act as FIRST MESSENGERS.
Chemicals generated Inside the Cell by Enzymes facing INWARD from the cell membrane are SECOND MESSENGERS. 
Question: What is the one exception to the rule that membrane enzymes face inward?
One exception to the Second Messenger rule that membrane enzymes face inward is at the skeletal neuromuscular junction.  Acetylcholinesterase projects OUTWARD into the synaptic cleft so it can metabolize acetylcholine. 
1.G proteins relay (shuttle) messages (signals) from receptors to enzymes.
2.The following substances are second messengers: cAMP, cGMP, calcium, calmodulin, IP3.
3.A given second messenger can produce different effects in different tissues. 
Question: What is an example of a second messenger action being tissue specific?
4.An increase in cardiac contractility is mediated by beta-1 adrenergic agonists and bronchodilation is mediated by beta-2 adrenergic agonists; both of these responses involve Gs and adenylate cyclase.
For example, increased cAMP in the heart increases Ca2+, causing increased contractility.  In bronchial smooth muscle, however, increased cAMP decreases Ca2+. producing smooth muscle relaxation (bronchodilation).  Concept: Second messenger action is tissue-specific.
Sodium-Potassium ATPase "Pump":
-keeps intracellular K+ high and intracellular Na+ low
-Three Na+ are extruded for two K+ imported.
Question: Name 2 Clinical Applications of the Sodium-Potassium ATPase Pump:
1.Insulin stimulates the Na+ - K+ pump, which is the reason insulin is an effective agent for treating HyperKalemia.  Insulin, by stimulating the Na+ - K+ pump, drives K+ into cells.  As you know, insulin also opens glucose channels, which permits the transfer of glucose into fat and skeletal muscle cells.  The glucose component of the glucose-insulin therapy for HyperKalemia prevents hypoglycemia.

2.Beta-2 adrenergic receptor agonists also stimulate the sodium-potassium pump.  This action explains, for example, why ritodrine (Yutopar) and terbutaline (beta-adrenergic receptor agonists) promote Hypokalemia.  Beta-adrenergic receptor agonists drive potassium into the cells by stimulating the sodium-potassium pump.
Know the ionic gradients!  Membrane excitability, action potentials and electrolyte disturbances will make much more sense...
Question: Well, what are they?
Ion  Extracellular   Intracellular mEq/L
Na+    145                10
K+         4              140
Ca2+      2               
Know: The resting membrane potential in excitable tissues (neurons, skeletal muscle cells, smooth muscle cells, and cardiac muscle cells) is determined mostly by K+.
Cells depolarize with acute HyperKalemia and hyperpolarize with actue Hypokalemia.  The resting potential of a typical neuron shifts from its normal value of -70 mV to a smaller value (e.g. -60 mV) with HyperKalemia, and to a larger value (e.g. -80 mV) with Hypokalemia.  Note: The negative sign (-) in front of the numerical value for the resting potential indicates the inside of the cell is negatively charges.
Know: In the neuron, voltage-gated sodium channels are found principally in the axon.
Note: When fast voltage-gated sodium channels are in the Inactivated state, another action potential cannot be fired no matter how intense the stimulus. 
Question: What are 3 clinical examples of this absolute refractory period/ "inactivated state"?
1.The high K+ concentration in Cardioplegia Solutions causes membrane depolarization, which "locks" the sodium channels in the inactive state so the heart electrically arrests.
2.Depolarization of the skeletal muscle motor end-plate by Succinylcholine causes the gated sodoium channels to become inactivated, thereby electrically arresting skeletal muscle.
3.Local Anesthetics interrupt nerve conduction by locking the sodium channel in the inactivated state.
1.K+ effux (through "leak" channels) is Most Responsible for Resting membrane potential.
2.Diffusion of Na+ ions into the cell is responsible for depolarizion of the axon.
3.Diffusion of K+ ions out of the cell is responsible for repolarization of the axon.
4.When the Na+ channel is in the inactivated state, another action potential cannot be fired--the neuron is in the absolute refractory period.
Tip: The sodium-potassium pump is stimulated by both insulin & epinephrine.
Hypopolarize is the same as depolarize.
Know: Motor nerves (efferents "exit") exit the ventral/anterior cord and sensory nerves (afferents "arrive") enter the dorsal cord.
"Sensory is Afferent is Dorsal= SAD"
1.The release of the neurotransmitter from all nerve terminals, including the motor nerve terminals, depends on the entry into the terminal of Ca++ ions.
"Calcium comes in, Neurotransmitter goes out."

2.Hypocalcemia is associated with a Decrease in the amount of neurotransmitter released, and Hypercalcemia is associated with an increase in the amount released.

3.Hypomagnesemia is associated with an Increase in the amount of neurotransmitter released, and hypermagnesemia is associated with a Decrease in the amount of neurotransmitter released.

4.Calcium and magnesium are Antagonistic at nerve terminals (presynaptically).
Know: It takes two molecules of acetylcholine to open the acetylcholine-gated channel of the skeletal muscle motor end plate.
When the channel of the motor end-plate opens, Na+ and Ca+ diffuse INTO the cell and K+ diffuses OUT.
Question: At the neuromuscular junction, does the presynaptic action of Succinylcholine enhance or antagonize its postsynaptic action?
Succinylcholine, by stimulating the presynaptic nicotinic receptor, augments the release of ACh.  Since the released ACh opens channels and depolarizes the motor end-plate like succinylcholine, the presynaptic action of succinylcholine enhances its postsynaptic action.  Know and understand this concept.
Duration of Action of Neuromuscular Blockers:
succs-very short, miva-short
atra,cisa,vec & roc-intermediate
rest: long
physiological properties of neuromuscular blockers:
A.100% ionized at physiologic pH
B.Very highly protein bound
C.Do NOT cross the blood-brain barrier (ions do not cross lipid bilayers)
D.Do NOT cross the placental barrier (ions do not cross lipid bilayers)
E.Trapped in the renal tubule after filtration because of high degree of ionization (NB: all muscle relaxants can be excreted by the kidney if other routes are unavailable)
Routes of Elimination of Neuromuscular Relaxants:
succs,miva,atra,cisa: METABOLISM
* Renal excretion can be important if primary and secondary routes are impaired/blocked
Know how muscle relaxants are metabolized:
1.Atracurium is eliminated by ester hydrolysis (nonspecific esterases, unrelated to plasma cholinesterase, perform ester hydrolysis) and Hofmann elimination (pH- and temperature-dependent degradation)

2.Cisatracurium is eliminated by Hofmann elimination only; nonspecific esterases are NOT involved in the elimination of cisatracurium.

3.Mivacurium is eliminated by plasma cholinesterase.
Know which muscle relaxants:
1.produce autonomic ganglionic blockade?
d-tubocurarine & metocurine block nicotinic receptors at the autonomic ganglia
2.elicit the release of histamine?
2.succs, miva, atra, d-tubo & meto release histamine.
3.produce bradycardia and why?
3.succs mimics the action of acetylcholine and directly stimulates muscarinic receptors of the SA node
4.produce tachycardia and why?
4.atra, d-tubo & meto produce reflex tachycardia; pan & gallamine competitively antagonize ACh, which are referred to as direct vagolytic, or more specifically antimuscarinic, actions.
5.produce significant hypotension?
5.succs, d-tubo & meto
6.produce significant hypertension?
6.panc & gallamine
What are the adverse effects of Succinylcholine?
a.release of K+ from the cells: plasma K+ concentrations may increase by 0.5 mEq/liter in normal pts & 5-10 mEq/liter in burn, trauma, or head-injury pts
b.muscle pains (myalgia)
d.AV block
e.increased IOP
g.increased ICP
h.prolonged resp paralysis if pt has atypical plasma cholinesterase (NB: plasma cholinesterase is also known as pseudocholinesterase or butyrocholinesterase)
k.increased intragastric pressure
Question: If you use a nerve stimulator on the right wrist of the pt with right-sided hemiplegia, will the twitch be less than, the same as, or greater than the twitch on the left?
The twitch on the right will be greater than on the left!!! Nicotinic receptors are UP-REGULATED on the right, hemiplegic side.  Know and understand this concept.
Malignant Hyperthermia (Hyperpyrexia): what is the defect in MH and how is it treated?
The defect in MH is in the sarcoplasmic reticulum (SR) of the skeletal muscle.  The SR fails to sequester Calcium, so sustained contractions with increased metabolism result.

Dantrolene is used to treat MH.  Dantrolene acts on the SR to decrease the release of Calcium to contractile proteins.
What is one of the earliest and most sensitive signs of MH?
One of the earliest and most sensitive signs of MH is an unexplained doubling or tripling in end-expiratory CO2.

Elevation of ETCO2 is one of the earliest, most sensitive and specific signs of MH...the initial signs of tachycardia result from sympathetic nervous system stimulation secondary
to underlying hypermetabolism and hypercarbia.

Sympathetic hyperactivity manifested by increased heart rate is also an early sign of increased metabolism.
What are agents that trigger MH?
Succinylcholine and halogenated inhalational agents (isoflurane, desflurane, halothane, enflurane, sevoflurane) can trigger malignant hyperthermia in genetically susceptible individuals.
Factors that Alter the Degree of Nondepolarizing Neuromuscular Blockade:
Block is usually INCREASED by factors with a couple of exceptions, what are they?
Block unchanged by penicillin, choramphenicol, and cephalosporins. 

Block unchanged in nondepolarizers by IV administration of corticosteroids.

Block decreased in nondepolarizers by pts treated chronically with anticonvulsants.

Block decreased in nondepolarizers by pts with thermal/burn injuries 10 days after injury, peaks at 40 days, and declines after 60 days.

Block is unchanged in depolarizer Succs by penicillin, choramphenicol, and cephalosporins.

Block unchanged in depolarizer Succs by halogenated inhalational agents.

What are 7 characteristics of Nondepolarizing Neuromuscular Blockers?
1.NO muscle fasciculations.
2.Block ANTagonized by anticholinesterases (Neostigmine etc.)
3.Amplitude of single twitch DECREASES with increasing intensity of block.
4.FADE occurs during TOF and Tetanic Stim.
5.Post-Tetanic Facilitation (POTENTIATION) = PRESENT.
6.TOF ratio < 70%.
7. T4/T1 < 70%
What are 7 characteristics of Depolarizing (Phase 1) Succs Block?
1.Fasciculations PRESENT.
2.Block ENHANCED by anticholinesterases (Neostigmine etc.)
3.Amplitude of single twitch DECREASES IN PROPORTION to severity of block.
5.TOF ratio > 70%.
6.Post-tetanic facilitation (POTENTIATION) is ABSENT.
What is Phase II block and Dual Blockade?
Phase II block or DESENSITIZATION Block, occurs with treatment of higher doses of Succs and/or prolonged exposure of motor end-plate to Succs.

Phase II block has the characteristics of a NONdepolarizing block; use of a peripheral nerve stimulator during phase II block will show FADE and Post-Tetanic Facilitation/Potentiation.

Dual blockade refers to simulataneous existence of both depolarizing (Phase I) and Phase II blockade.

When should timing of reversal of Nondepolarizing Neuromuscular Blockade occur?
Antagonism of neuromuscular blockade should normally NOT be attempted when blockade is intense, because reversal will often be inadequate, regardless of the dose of antagonist administered. 

Reversal can be attempted when one twitch is elicited.

In general, antagonism should NOT be initiated before at least TWO, preferably THREE or FOUR, responses are observed.
1.Acetylcholine is the neurotransmitter released from somatic motor nerves, preganglionic sympathetic nerves, preganglionic parasympathetic nerves, and postganglionic parasympathetic nerves.
2.With one exception, norepinephrine is released from all sympathetic postganglionic nerves.  The exception is the SWEAT GLANDS.  Acetylcholine, not norepinephrine, is released to sweat glands from sympathetic postganglionic nerves.
3.The adrenal medulla is innervated by sympathetic preganglionic neurons;hence, acetylcholine released from sympathetic preganglionic neurons elicits the release of hormones (notably epinephrine and norepinephrine) from the adrenal medulla.
1.There are 2 major subtypes of cholinergic receptors: nicotinic and muscarinic.
2.Muscarinic receptors are found peripherally in tissues innervated by parasympathetic postganglionic neurons.
3.Nicotonic receptors are found peripherally in the motor end-plate of skeletal muscle and in cell bodies of both sympathetic and parasympathetic postaganglionic neurons. 

Nicotinic receptors respond to ACh or ACh agonists (e.g., Succs) in a BIphasic fashion.  In small doses, ACh stimulates nicotinic receptors of postganglionic sympathetic and parasympathetic neurons as well as nicotinic receptors of the skeletal muscle end-plate to cause depolarization (this is normal response).

In high doses and/or with prolonged exposure, the nicotinic receptor becomes DESENSITIZED to Succs and the postsynaptic membrane becomes INEXCITABLE.  This is called Phase II block, or DESENSITIZATION block, when it occurs at the motor end-plate of skeletal muscle.

Clinical example: Prolonged and/or high dose exposure to Succs causes desensitization of postsynaptic nicotinic receptors at the neuromuscular junction (Phase II Block).
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