Pharm2Final Flashcards
What are the three naturally occurring catecholamines?
- epinephrine
- norepinephrine
- dopamine
What are the two synthetic catecholamines?
- isoproterenol
2. dobutamine
What are the six steps of cholinergic transmission?
- synthesis
- storage
- release via Ca++ mediated exocytosis
- binding
- degradation
- recycling
Sympathomimetic drugs have their effect on adrenergic receptors located in the _____ and _____.
CNS and the ANS
What is the nuerotransmitter for pre-ganglionic adrenergic neurons in the SNS?
Ach
What are the required neurotransmitters for sympathomimetic receptor types alpha and beta?
epi or norepi
What is the effects of alpha 1 stimulation and where are the receptors found at?
POST SYNAPTIC
vasoconstriction, mydriasis, relaxation of GI, contraction of GI sphincters, contraction of bladder sphincters
What is the effects of alpha2 stimulating and where are the receptors found?
PRESYNAPTIC-inhibition of NE
POSTSYNAPTIC-platelet aggregation, hyper polarization of cells in the CNS, sedation
Adrenergic receptors specifically bind to what two neurotransmitters?
epi and NE and they are activated by them
What is the selected agonist action of Beta 1?
increased myocardial contractility
What are 4 agents with beta 1 properties?
- isoproterenol
- dobutamine
- epi
- NE
What are 2 beta 1 antagonist?
- metoprolol
2. atenolol
What is the selected Beta 3 agonist action?
lipolysis—>”burn fat”
How is the action of catecholamines terminated?
by repute into the postganglionic sympathetic nerve endings
Sympathomimetics mimic actions of…..?
endogenous neurotransmitters, epi, NE and dopamine
Direct acting sympathomimetic agonist act on what receptors?
post-synaptic
Synthetic non-catecholamines activate adrenergic receptor how?
by evoking release of NE from POST GANGLIONIC sympathetic nerve endings
elicit mostly a and b-1 as NE is a weak b-2 agonist
Indirect acting sympathomimetics require _____ _____ to produce effect.
endogenous catecholamines; little activity if catecholamines are depleted
Do direct acting sympathomimetics require endogenous catecholamines to produce effect?
no; they activate even if catecholamines are depleted
Where is the location of the adrenergic receptors that direct acting sympathomimetics act upon?
post-synaptically on adrenergic receptors
Direct acting sympathomimetics include catecholamines and synthetic non-catecholamines(T/F)?
true
What are three uses of alpha 1 agonist?
- hypotension-to increase BP during anesthesia
- ophthalmic preparations-to induce mydrasis
- cough and cold preparations-induces constriction of nasal mucosa, decreases resistance to air flow
T/F-Direct acting alph agents-synthetic agents that directly activate alpha-1 adrenergic receptors?
true
What is the dose of Precedex?
1 mcg/kg bolus for 10 minutes
0.2 - 1 mcg/kg/hour maintenance
What are four examples of direct acting beta-1 agonist?
- dopamine
- dobutamine
- epinephrine
- isoproterenol
Stimulation of beta-1 receptors induces positive(3) effects?
- chronotropic
2, dromotropic - inotropic
How is epinephrine synthesized?
tryosine—>DOPA—>dopamine—>NE—>epi
How is epi released?
- SNS acting vai splanchnic nerves to the adrenal medulla stimulate the release of epi
- calcium triggers exocytosis of chromatin granules and realize of epi and NI into the bloodstream
Do indirect sympathomimetics act upon beta-2?
nope
What is THE adrenergic neurotransmitter?
norepinephrine
Where is NE released from?
released from presynaptic vesicles of postganglionic sympathetic nerve endings
What is the effects of NE release?
- equal to epi at beta-1 with very little beta-2 action
- potent alpha-1 producing intense vasoconstriction in arterial and venous vascular beds
- causes >SBP, >DBP, >MAP
- has no bronchodilating effects
By what action does NE increase BP?
primarily by increasing the SVR
What can be a reflex triggered by NE induced increase in SVR?
reflex bradycardia
What types of receptors does NE bind to causing stimulation of alpha and beta?
adrenergic receptors
What structure is the origin of most NE pathways in the brain?
Locus ceruleus
Is norepi released from pre-ganglionic SNS neurons or post-ganglionic?
post-ganglionic
Ach is released pre-ganglionic
What is the steroisomer of NE?
Levophed
How is NE synthesized?
synthesized in te adrenal medulla from the amino acid tyrosine
tyrosine—>L-dopa—>dopamine—>NE
How is the action of NE terminated?
either by degradation of NE or by NE UPTAKE BY SURROUNDING CELLS
After being released into the synaptic cleft, NE acts upon what type of receptors?
adrenergic
What is two ways uptake is done with NE?
- pre-synaptically
2. by non-neuronal cells in the vicinity
What is NE mechanism of action?
acts on target cells by binding to and activating adrenergic receptors.
unlike ep, NE does not activate beta-2 receptors—>just alpha-1, alpha-2 and beta-1
T or F: NE has different actions based on different cell types?
true
What types of patients is NE useful with?
NI is used to treat patients in vasodilatory shock states such as septic shock and neurogenic shock
Dopamine is a CNS neurotransmitter that is a _____ derivative.
phenethylamine
There are five types of dopamine receptors, how many of them have clinical significance?
only 2, D1,D2
Does dopamine have direct or indirect adrenergic action?
both
At what part of the NMJ does dopamine1 act and what is the affect?
POST-SYNAPTIC: vasodilation of renal, mesenteric, coronary and cerebral blood vessels
At what part of the NMJ does dopamine2 act and what is the affect?
PRE-SYNAPTIC: inhibits the release of NE
POST-SYNAPTIC: weak vasoconstricton
Dopamine actions include?
> CO
HR
SBP
Can dopamine cross the BBB?
nope
To increase dopamine in brains of patients with diseases such as Parkinson’s and dopa-responsive dystonia, _____ can be given because it crosses the BBB.
L-DOPA(levo-dopa)
Describe dopamine synthesis
synthesized by adrenal medulla —>tyrosine—>L-DOPA—>dopamine
How is dopamine stored and released?
In neurons, dopamine is packaged after synthesis into vesicles, released into synapses in response to pre-synaptic action potentials
How is dopamine inactivated?
by repute via dopamine transporter DAT
How is dopamine broken down?
by catechol-o-methyl transferase(COMT) and monoamine oxidase(MAO)
dopamine not broken down is repackaged into vesicles for reuse
Dopamine dosing?
-2-5 mcg/kg/min:
binds D1 receptors, dilating blood vessels, increasing blood flow to renal, mesenteric, coronary and cerebral arteries
-5-10 mcg/kg/min:
postitive inotropic and chronotropic effects via increased beta-1 receptor activation. Used in patients with shock or heart failure to increase CO and BP.
-10-20 mcg/kg/min:
dopamine causes vasoconstriction, increases SVR and increases BP through alpha-1 receptor activation.
By what effect does “renal dose” dopamine prob work?
by increasing the CO
McCarver not a believer in renal dose dopamine
What is the most potent activator of beta adrenergic receptors?
Isoproterenol
Does Isoproterenol directly affect the BP?
NO-has no alpha affect!
increased SBP is indirectly from greater CO, will see lower MAP and decreased DBP due to reduced SVR
What is Isoproterenol used for?
- greater HR
- increased myocardial contractility
- cardiac automaticity
- bronchodilation
- reduction in PVR
use with post heart transplant patients due to deinnervation of the orthotropic heart transplant
mostly seen in heart blocks now
What particular caution should be observed when using Isoproterenol?
caution with low DBP and reduced coronary perfusion since increased HR causes increased myocardial oxygen consumption
What is the primary use of Isoproterenol?
bradycardia and heart blocks
- resistant bradyarrhythmias when pacing is not available
- pharmacologic pacing for torsade de pointes(polymorphic ventricular tach)
can also be used as a bronchodilator(very rare)
Isoproterenol caused what three effects?
- chrontropic
- dromotropic
- inotropic
What are some contraindication for use of Isoproterenol?
angina, pre-existing arrhythmias, tachycardia or AV block caused by cardiac glycoside intoxication. Ventricular arrhythmias due to AV nodal block
*significantly increased myocardial oxygen demand—>can cause vasodilation(beta-2 effect)
What is the dose for Isoproterenol?
usual effective dose 0.-2 mcg/kg/min
What type of catecholamine is Dobutamine?
synthetic
What is Dobutamine used to treat?
Sympathomimetic used to treat CHG and cariogenic shock.
-Used to treat acute and chronic heart failure as with heart surgery, sepsis and cardiogenic shock
What is the primary action of Dobutamine?
direct stimulation of beta-1 receptors
In what specific scenario is dobutamine not useful and why?
not useful in ischemic heart disease because it may increase HR, potentially increasing myocardial oxygen demand
also: +dromotrope so be careful with atrial fibrillation as HR may markedly increase—>so prob is contraindicated in patients with A-fib
Dobutamine best used in combo with other drugs like _____ in the presence of _____.
vasodilators; increased afterload
What are the results of using dobutamine?
increased CO
decreased atrial filling pressure
increased HR
increased SBP
allegedly a coronary artery vasodilator with no endogenous catecholamine release like dopamine
Describe the racemic mixture of dobutamine.
Dobutamine is given as a racemic mixture for both + and - isomers.
-The + isomer is a potent beta-1 agonist
-the - isomer is an alpha-1 agonist
Dobutamine also has mild beta-2 agonist activity
What are the specifics on Dobutamine dosing?
- Infusion should be started at low rates, 0.5-1.0 mcg/kg/min and titrated by patients response including SBP, HR and invasive monitoring
- Optimal infusion rates typically 2-10 mcg/kg/min
- use the lowest rate you can get away with*
What are some results are usually seen with dobutamine?
- a 10-20 mm increase in SBP and increase in HR of 5-15 beats/min
- 5% of patients experience PVC’s-dose related
What is the drug classification of phenylephrine?
Synthetic non-catecholamine
What is the principal effect of phenylephrine?
- direct alpha-1 effect with only a small part via indirect release of NE
- minimal if any beta effect
venoconstriction > arterial constriction
mimics NE but is less potent and longer lasting
What cardohemodynamic effects are seen with the use of phenylephrine?
- increases SBP
- decreases CO
- lowers HR(reflex)
- raises PAP
- reduced CO most likely from baroreceptor-mediated reflex bradycardia rather than increases in after load*
- may impair LV global function when given rapidly to anesthetized patients(1mcg/kg)*
- can be used to treat SVT(500 mcg bolus)
Describe phenylephrine dosing
- IV infusion(usual initial rate): 100-180 mcg/min
- Usual maintenance rate: 20-60 mcg/min
- Max rate: infusion rates as high as 10 mcg/kg,min may be required in shock
- Adult IV bolus therapy: usual dose is 100 mcg and repeat as needed
- SVT(PSVT): 0.5 mg(500 mcg) rapid IV push, subsequent doses may be increased in increments of 0.1-0.2 mg
wean as soon as possible as will hurt end organ perfusion
What is the novelty of Precedex?
unusual in its ability to provide sedation without causing respiratory depression
What type of agonist is Precedex?
like clonidine it is an alpha-2 adrenergic agonist
By what mechanism does Precedex decrease BP?
decreases sympathetic tone, with attenuation of neuroendocrine and hemodynamic responses to surgery
reduces anesthetic and opioid requirements
What type of compound is Precedex?
imidazole compound
What type of pharmacological active isomer is Precedex?
pharmacologically active dextroisomer of medetomidine
The pharmacological isomer of Precedex causes?(4)
- hypotension
- bradycardia
- sedation
- analgesia
Other responses to the activation of alpha-2 receptors by Precedex include….
- decreased salivation, decreased secretion and decreased bowel motility
- contraction of vascular and other smooth muscle
- inhibition of renin release
- increased glomerular filtration and increased secretion of sodium and water in the kidney
- decreased intraocular pressure
- decreased insulin release from the pancreas
What are the indications for Precedex?
- indicated for sedation of critically ill and nonintubayted patients requiring sedation for surgery or procedures short-term.
- useful as an adjunct for sedation and general anesthesia
What are the contraindications of the use of Dexmedetomidine?
- no absolute contraindications
- Very expensive
- caution with boluses due to peripheral alpha-2 receptor stimulation with resulting hypertension and bradycardia(may see hypotension with loss of sympathetic tone)
- high cost relative to generic medications
Individual variablity in HR and BP effects, as well as the sedative effects of the drug
Describe the drug Methoxamine, its classification, what receptors it stimulations and why its used
- direct acting synthetic non-catecholalmine
- alpha agonist
- used in cath lab and tx for SVT
Describe the drug Clonidine, its classification, what receptors it stimulations and why its used
- direct acting
- selective alpha-2 agonist
- used for the treatment of HTN and opioid withdrawal
Describe the drug Terbutaline, its classification, what receptors it stimulations and why its used
- direct acting
- beta-2 agonist
- treatment of asthma and to slow uterine contractions
Describe the drug Albuterol, its classification, what receptors it stimulations and why its used
- direct acting
- beta-2 agonist
- acute bronchospasm
Describe the indirect adrenergic agonist Amphetamines
- resemble ephedrine in their alpha and beta receptor stimulation, however differ in their intense CNS activity
- reflects the release of NI stores in the CNS
- clinical uses include ADD, anoretics, troops in combat
- Tyramine found in fermented foods(cheese) metabolized by MAO and may cause hypertensive crisis in patients with MaOI
Is Ephedrine a direct acting synthetic non-catecholamine, or an indirect acting synthetic non-catecholamine and why?
Ephedrine is a mixed acting synthetic non-catecholamine.
- endogenous release of NE(indirect)
- Direct stimulation of adrenergic receptors
**stimulates alpha and beta receptors
What are the two affects responsible for prolonged duration of Ephedrine?
- slow inactivation
2. slow excretion
Where on the NMJ is Ephedrine active?
presynaptically causing the release of NE—>primary beta effects
What are two things that Ephedrine may cause besides the intended affects?
- mydriasis
2. CNS stimulation
Can Ephedrine be given IM?
yes
Does Ephedrine have good absorption from the stomach?
yes
The ____ of Ephedrine will be the best due to ______.
first, endogenous catecholamine depletion
What hemodynamic affects will be seen with Ephedrine administration?
- CV effects are similar to Epi except milder
- SBP increased are less intense but last 10 times longer, takes 250X an ephedrine dose to equal an epi dose
- increased SBP, DBP, HR & CO
- Renal and splanchnic blood flows are decreased(due to alpha effect), coronary and skeletal muscle blood flows are increased
What is the principle mechanism for the CV effects of Ephedrine?
- principle mechanism of CV effects is increased myocardial contractility due to activation of beta-1 receptors
- in the presence of beta blockage, predominant CV effect may be a receptor stimulation
In the beta blocked patient what effect will you primarily see when administering Ephedrine?
alpha cause they are beta blocked
Is Vasopressin an adrenergic agent? Does it bind to alpha or beta receptors?
No it is a:
- peptide hormone derived from pre-prohormones synthesized in the hypothalamus
- stored in the posterior pituitary for the release into the bloodstream or directly into the brain
What is the dose of Vasopressin and why give it?
- given as single IV dose of 40 units
- Given as an alternative to epi for treatment of shock-resistant v-fib or pulseless v-tach
used to increase SVR
What are the three arginine Vasopressin receptor types?
- AVPR1A-vasoconstriction, gluconeogenesis, platelet aggregation, coagulation
- AVPR1B-ACTH secretion in response to stress
- AVPR2-anti diuretic effect
Where are Vasopressin receptors present in the body?
brain, liver, kidney and vascular
What effect does Vasopressin have on the body?
- Vasopressin is released when the body is dehydrated, causing kidneys to conserve water by decreasing UOP
- In higher {}, vasopressin raises BP by increasing SVR
- Vasopressin increases permeability to water of distal convoluted tubules and collecting tubules in nephrons allowing water reabsorption and excretion of small volumes of more {} urine
- ANTI-DIURETIC drug
What are the hemodynamic reasons to use Vasopressin?
for hemodynamic support in septic shock
What is the dose for vasopressin?
- For shock, bolus of 0.5-20 units followed by an IV infusion rate of 0.01-0.4 units/minute
- doses above 0.04 units/minute do not consistently improve hemodynamics and may contribute to adverse events
- adding vasopressin to NE may allow reduction of NI doses
What is the blood-gas partition coefficient of Isoflurane?
1.46
What is the blood-gas partition coefficient of Nitrous Oxide?
0.46
What is the blood-gas partition coefficient of Desflurane?
0.42
What is the blood-gas partition coefficient of Sevoflurane?
0.69
What is the MAC value of Isoflurane?
1.17%
What is the MAC value of Desflurane?
6.6 %
What is the MAC value of Sevoflurane?
1.8%
What is the MAC value of Nitrous Oxide?
104%
What is the action of anticholinergic drugs at the NMJ?
Anticholinergic drugs COMPETITIVELY ANTAGONIZE effects of acetylcholine at cholinergic POST-GANGLIONIC sites known as muscarinic receptors
What three terms describe belladonna compounds?
- anticholinergic
- antimuscarinic
- parasympatholytic
Where are muscarinic cholinergic receptors found and what is the MOA in each place?
- heart(increase HR)
- salivary glands(decrease secretion)
- GI/GU smooth muscle(decrease)
What is acetylcholine?
neurotransmitter at post-ganglionic nicotinic receptors of the NM junction and the autonomic ganglia
Anticholinergics in usual doses have no effect on post-ganglionic NICOTINIC receptors(t/f)
true
Anticholinergics are specific to which receptors?
muscarinic
Describe the classification of atropine and scopolamine.
naturally occurring tertiary amine anticholinergic drugs
they will cross BBB
What is the classification of glycopyrrolate.
semi-snthetic quaternary ammonium compound
*will NOT CROSS BBB
Natural occurring anticholinergics are _____ _____, Synthetic anticholinergics are _____ _____ _____.
tertiary amines
quaternary ammonium compounds
If an anticholinergic is described as alkaloid what does that mean?
it is a tertiary amine…it has CNS effects meaning it can cross the BBB….contains tropic acid and it is a racemic mixture
**atropine/scopolamine
If an anticholinergic is not an alkaloid what does that mean?
it is a quaternary ammonium compound…has no CNS effects…will not cross the BBB…contains mandolin acid and is not a racemic mixture
glycopyrrolate
What is the name of the racemic mixtures of atropine and scopolamine? Of the two racemic mixtures which exerts anticholinergic effects?
- dextro
- levorotary
Levorotary form exerts anticholinergic effects
What type of acid dos glycopyrrolate contain?
madelic acid
What type of acid does atropine and scopolamine contain?
tropic acid
What is the mechanism of action of anticholinergics?
- Anticholinergics combine reversibly with muscarinic cholinergic receptors and prevent acetylcholine from binding
- Anticholinergic drugs bind to muscarinic receptors without eliciting a muscarinic response
How many types of muscarine cholinergic receptors are there…what are their names?
There are 5 muscarinic cholinergic receptors
m1,m2,m3,m4,m5
What is the function of the M1 muscarinic cholinergic receptor?
CNS, stomach, inhibits NE release
What is the function of the M2 muscarinic cholinergic receptor?
SA, AV nods, Purkinje fibers, reduces myocardial oxygen demands and relaxes bronchial smooth muscles
What is the function of the M3 muscarinic cholinergic receptor?
CNS, bronchial smooth muscle, glands, vascular beds, iris, ciliary body, GI
anti-sialogoge and drying of bronchial secretions elicited with lower doses of anticholinergic than M2 receptor effects of increased HR and CNS changes
for example—>0.1 - 0.2 mg glycopyrrolate before an awake intubation without significantly increasing HR
What is the function of the M4 and M5 muscarinic cholinergic receptor?
CNS
It takes a _____ dose to inhibit M1 receptor mediated H+ secretion in gastric secretions
huge
In what type of patient should scopolamine by avoided in?
Mydriatic effects of scopolamine are greater than atropine-scopolamine avoided in glaucoma patients
Glycopyrrolate safest has least effect on pupil size
Which of the anticholinergic agents has the greatest antisialagogue and ocular effects?
scopolamine
What is the primary reason to give scopolamine to preop open heart patients?
decreased metabolic oxygen requirements…..atropine causes no change and glycopyrrolate increases oxygen demand.
Which anticholinergic is most potent in decreasing reticular activity?
scopolamine is 100X more potent than atropine in decreasing reticular activity
Does glycopyrrolate have any sedative effects?
no it does not cross the BBB
What reverses restlessness/somnolence due to tertiary amine anticholinergic drugs?
Physostigmine
Which anticholinergic is a good choice when sedation and potent antisialagogue actions is desired?
Scopolamine
Scopolamine>glycopyrrolate>atropine(antisialagogue action)
By what action does atropine treat intraoperative bradycardia resulting form vagal activity?
Atropine 15-70 mcg/kg increased HR by blocking ACh effects on the SA node.
Will anticholinergics alter HR in the de-innervated(transplanted) heart?
no
Antagonism of non-depolarizer NMB with antichozlinesterases requires co-administration of atropine or glycopyrrolate to…….
counteract parasympathomimetic effects of antichlinesterase drugs
scopolamine not used to reverse**
High doses of anticholinergics needed to decrease H+ secretions are associated with?
unpleasant to dangerous side effects
What is the drug of choice for treatment of central cholinergic syndrome?
physostigmine
What is the definition of postoperative residual NMB?
- TOF ratio < 0.9 after reversal
- clinical weakness
Smaller dose of neostigmine prudent if…..?
time since relaxant is less than hours
Cholinesterase inhibitors Hydrolyze how many molecules of ACh per minute?
300,000
What is the three mechanisms of actions of cholinesterase inhibitors?
- weak agonist action
- formation of desensitized receptor complex intermediates
- alteration of conductance properties of active channels
Edrophonium, neostigmine and pyridostigmine are quaternary ammonium compounds which means?
- they are poorly lipid soluble
- minimal penetration through lipid barriers(GI tract, placenta, BBB)
If edrophonium, neostigmine or pyridostigmine administered how is the mechanism of action impacted?
inhibition achieved via different mechanisms
Neostigmine and Pyridostigmine form ____ ____ at ___ sites of cholinesterase.
carbamyl-ester complexes at esteratic sites of cholinesterase
Neostigmine and Pyridostigmine increase {} of _____ around _____.
endogenous ACh around cholinoreceptors
What are two NMB reversal mechanisms?
- increasing ACh in junctional cleft changing agonist-antagonist ratio
- longer ACh life within cleft due to increased ACh
Both Neostigmine and Pyridostigmine increase ACh inactivation by forming?
covalent bonds
Of Neostigmine and Pyridostigmine which is most potent and which has the more rapid onset of action?
Neostigmine
What describes the activity of the metabolites of Neostigmine?
metabolies 1/10 activity of neostigmine(very weak)
What is the Vd of Neostigmine?
0.7 L/kg in healthy patient(poor lipid soluble), increases to 0.8 L/kg with renal failure
Pyridostigmine is the cholinesterase inhibitor with the?
longest onset and duration
What type of bond does Edrophonium form?
- does not form covalent bonding
- binds reversibly with negatively charged enzyme sites by ELECTROSTATIC ATTRACTION of positively charged nitrogen
What are some pharmacologic causes of prolonged paralysis?
- Aminoglycoside toxicity
- penicillin toxicity
- steroid myopathy
- antihypertensives(Ca+ channel blockers, B-blockers, Lasix)
- antidysrhythmics(quinidine/procainamide/LA)
- Aminoglycosides abx(Polymyxin B/Clindamycin/Tetracycline)
What is the dose, speed of action, duration of action and most common SE of Neostigmine?
25-75 mcg/kg
5-15 minutes
45-90 minutes
+PONV
What is the dose, speed of action, duration of action and most common SE of Pyridostigmine?
100-300 mcg/kg
10-20 minutes
60-120 minutes
slow onset, long duration
What is the dose, speed of action, duration of action and most common SE of Edrophonium?
50-1000 mcg/kg
5-10 minutes
30-60 minutes
not for deep block, rapid
The number of twitches (TOF count) correlates with degree of NMB. T4 disappears at ___ depression of T1.
T3 disappears at ___ depression of T1.
T2 disappears at ___ depression
75%
80-85%
90%
reversal of residual NMB safety achieved when TOF count is 3 or greater
Traditionally, it had been accepted that a TOF ratio of _______ was an indication of adequate reversal. However it has been challenged recently and it is now thought that a TOF ratio of ___ should be achieved before extubation.
- 7 or greater
0. 9
The use of tetanic stimulation is limited due to?
pain
During partial depolarizing block, is fade observed with tetanic stimulation?
no
What is the NMJ neurotransmitter?
Acetylcholine
ACh is released in the synaptic cleft as packets or?
quanta
How many molecules are in a quanta?
1000
What are the 5 post junctional nicotinic cholinergic receptors?
- alpha1
- alpha2
- beta
- gamma
- delta
How many receptors are opened by the burst of ACh at the nmj?
- at least 400K
- the current flows through open receptors, depolarizes end-plates, starts action potentials
What is the basis for NM transmission?
the flow of ions
NDNB show preference for?
1 of 2 alpha subunits
What receptors of the nicotinic receptors are the sites of action for NMB agents in addition to binding ACh?
the 2 alpha units
If 2 alpha subunits are occupied simultaneously, ion channel opens and?
fasciculations occur
NDNB act on ?
- NDNB act by combining with nicotinic cholinergic receptors without any activation of ion receptor channels
- Act on POST-JUNCTIONAL alpha subunits
Occupation of less than 70% of nicotinic cholinergic receptors……..?
no evidence of block by single twitch test
Neurotransmission fails when _______% of alpha subunit post-junctional nicotinic cholinergic receptors are blocked.
80-90%
Non-depolarizing NMB characteristics
- decreased response to single twitch
- fade during tetanus
- TOF ratio < 0.7
- post tetanic potentiation
- potentiation of other NDNB
- antagonism by anticholinesterase drugs
- NO FASCICULATIONS
There is no detectable block until _____% of receptors are occupied?
75 - 85 %
Paralysis is complete at _____% receptor occupancy?
90 - 95%
During non-depolarizing block response to single twitch stimulation is not reduced until at least ____% of receptors are occupied?
75 - 80%
Single twitch does not detect block of < than ___, limiting clinical applicability of single twitch stimulation?
<70%
With nerve stimulation monitoring, first twitch is accurate only if how many seconds have elapsed since previous stimulation?
10 seconds
With nerve stimulation monitoring, disappearance of the fourth response after TOF stimulation corresponds to?
70 - 75% single twitch depression
With the use of NDNB, post-tetanic facilitation can be repeated every?
10 - 12 seconds
With tetanus fade is first noted at __% receptor occupancy?
70%
How does Hemiplegia affect the use of NDNB?
resistance to non-depolarizers develops within 2-3 days, central inhibition
always monitor the unaffected side
What kind of response do NDNB agents have on those suffering from Parkinsons or multiple sclerosis?
normal
What affect does NDNB agents have on burn patients?
> than 30% body surface burns acquire NDNB resistance
- begins 10 after injury
- peaks @ 40 days
- declines after 60 days
What are the three metabolites of Vecuronium?
- 3-desacetyl vecuronium(1/2 as potent as vecuronium)
- 17-desacetyl vecuronium(1/10 as potent)
- 3,17-desacetyl vecuronium(1/10 as potent)
Can vec be used in OB patients?
yes, insufficient vec {} cross placental barrier to produce significant effects on newborn
Does vec alter intraocular pressures?
no
Does vec trigger MH?
no
Duration of action of vec may be _____ in patients over 130% of ideal weight?
130%
What makes rocuronium special of the NDNB?
the only ND that serves as an alternative to succinylcholine for rapid sequence.
Which nerve response should be monitored for best intubating conditions?
obicularis oculi
Which nerve response should be monitored for the best return of breathing?
adducter pollicis
What classification of ND is cisatracurium?
Benzylisoquinolinium
What is responsible for principle degradation with cisatracurium?
Hoffman elimination
With cisatracurium, NMB is easily maintained by
constant rate infusion without diminishing over time
Hoffman eliminaton accounts for _____ of clearance, renal clearance accounts for ____?
77%, 16%
in ESRD, no alteration in neuromuscular blocking profile
What is the mechanism of action of Succinylcholine?
- attaches to alpha subunit of nicotinic cholinergic receptors
- mimics action of acetylcholine
- depolarizes the post-junctional membrane
With Succinylcholine, sustained receptor ion channel opening and depolarization of post-junctional membranes caused K+ leakage from cell interiors…..how much increase in serum K+ is seen?
0.5 mEq/L
Succinylcholine dosing: > than 2 mg/kg, repeated doses and succinylcholine infusions may cause?
Phase II block
With Succinylcholine, what are four characteristics of a Phase I block?
- reduced response to single twitch
- reduced but sustained response to tetanus
- TOF ratio > than 0.7
- no post-tetanic facilitation
When Succinylcholine is metabolized, what are its two metabolites?
- succinic acid
2. choline
Succinylcholine is contraindicated in what four types of patients? Succinylcholine administration to such individuals may result in what?
- major burns
- multiple trauma
- extensive denervation of skeletal muscle
- upper motor neuron injury
SEVERE HYPERKALEMIA which may result in cardiac arrest
Of the many possible adverse reactions to Succinylcholine, most will be minimized by pretreatment by a NDMB….which will not?
HYPERKALEMIA
Although Succinylcholine has no direct effect on the myocardium, what does it stimulate which can lead to what?
- Succinylcholine stimulates autonomic ganglia and muscarinic receptors which cause changes in cardiac rhythm including cardiac arrest.
- Changes in rhythm may result from vagal stimulation or from hyperkalemia, particularly in children.
When is Succinylcholine dysrhythmias most likely to occur?
- most likely to occur when a second succinylcholine dose follows 5 minutes after the first dose
- due to succinylcholine actions at cardiac muscarinic cholinergic receptors where succinylcholine mimics acetylcholine effects
- atropine will not treat this bradycardia
- pretreatment with a NDNB may prevent the occurrence of cardiac dysrhythmias
If a healthy appearing kid develops cardiac arrest after succinylcholine not due to inadequate ventilation, oxygenation, or anesthesia OD, immediate treatment for hyperkalemia should be instituted. What are the 4 steps to immediately take?
- IV calcium
- bicarbonate
- glucose with insulin
- hyperventilation
Tetanic response is fully sustained with the TOF ratio was_____. When the ratio is _____, variable degrees of fade of tetanus were evident.
above 0.7, less then 0.7
Describe the significance of having no twitches on TOF.
100% blocked, suitable for intubation
Describe the significance of having 1 twitch with TOF
90% blocked, mechanical ventilation
Describe the significance of having 2 twitches with TOF
80-90% blocked, short term relaxation
Describe the significance of having 3 twitches with TOF
75-80% blocked, maintenance doses needed
Describe the significance of having 4 twitches with TOF
0-75% blocked, rapid cholinesterase inhibitors reversal
A TOF ratio of ____ or _____ reliably indicates the recovery of thesinale twitch to control height and a sustained response to tetanic stimulation
- 7 or higher
* reliance on the recovery of thesinale twitch to control height as a criterion of spontaneous return to normal clinical neuromuscular function may be misleading*
What are the characteristics of a phase II block(5)?
- decreased single twitch response
- fade on tetanus
- TOF ratio < 0.7
- post-tetanic facilitation
- fade on TOF
What is the initial sign of phase II block?
tachyphylaxis
With plasma cholinesterase, a Dibucaine # of 80 means what?
80% inhibition of plasma cholinesterase activity—>NORMAL
With plasma cholinesterase, a Dibucaine # of 20 means what?
20% inhibition of plasma cholinesterase activity-found 1 out of 3200 patients—>means they are homozygous for an atypical plasma cholinesterase variant.
in these patients, succinylcholine last up to 3 hours in normal doses
With plasma cholinesterase, a Dibucaine # of 40-60 means what?
40-60% inhibition of plasma cholinesterase activity-found in 1 of 480 patients—>means they are heterozygous for atypical plasma cholinesterase.
These patients may have prolonged succinylcholine blocks lasting up to 30 minutes.
The dubucaine # is an indicator of _____ of plasma cholinesterase, not _____.
quality not quantity
What is the pharmacologic effects of a neuromuscular blocking agent?
-interrupts nerve impulse transmission at the neuromuscular junction.
What are two classifications of NMB?
- depolarizers
- non depolarizers
What are the two classifications of non-depolarizering NMB and what drugs belong to each class?
- benzylisoquinolinium(nimbex/atracurium(nimbex’s daddy)
- aminosteroid compounds(pancuronium/rocuronium/vecuronium)
How is the equal potency between NMB drugs measured ?
by dose required to suppress 95% of single twitch responses
What are the principle sites we measure NMB and what types of twitch at each site?
- adductor pollicis(slow twitch)
- obicularis oculi(fast twitch)
Where is NMB affect seen first and last?
- small rapidly moving skeletal muscles first(loss of eye lid reflex)
- diaphragm last(first muscle that returns)
Non-depolarizing NMB onset more rapid yet less intense at laryngeal muscles than diaphragm
Laryngeal muscles(fast twitch) equilibrate _____ with plasma NMB {} than slow twitch muscles(adductor pollicis)
more rapidly
- laryngeal muscle relaxation is brief
- laryngeal relaxation declining by time of maximal diaphragmatic relaxation with short and intermediate action NDNB*
- Dose required to produce a degree of NMB at diaphragm is 2 X that required for an equal block at adductor pollicis or obicularis oculi*
Adductor pollicis monitoring is best for monitoring what?
diaphragm relaxation
Obicularis oculi monitoring is best for monitoring?
laryngeal relaxation
Single-twitch response gives what type of data?
POST-junctional data
Tetanus and TOF gives what type of data?
PRE- junctional data
Do depolarizing NMB have fade with TOF?
no
fade will differentiate between depolarizer vs. non-depolarizer NMB
The positive TOF fade with non-depolarizing NMB is known as ?
Wedensky inhibition
continous refractory state preventing repolarization…occurs when nerve is stimulated with high electrical frequencies and ends when application of current stops
Neuromuscular blockers have quaternary ammonium groups which make them:?
- highly ionized
- water soluble at physiologic pH
- poorly lipid soluble
- small volume of distribution(due to lipid insolubility)
What lipid membranes are not crossed by NMB(4)?
- BBB
- renal tubular epithelium
- GI
- placenta
The rate of disappearance of long acting NMB is due to?
rapid initial decline is due to redistribution followed by slower decline from clearance
How does hypovolemia affect NMB?
equal drug doses produce exaggerated effects due to greater plasma concentrations
For laryngospasm, doses as small as ___ of succinylcholine are effective.
0.1 mg/kg
TOF < than ____ reflects adequate return of skeletal muscle strength for spontaneous ventilation.
0.7
What is the only NDNMB with an onset similar to succinylcholine?
rocuronium
NMB selection is determined by
- speed of onset needed
- duration of action needed
- drug effects at other than NMJ
The last muscles(2) paralyzed are the?
intercostals and diaphragm
NMB affect _____ before muscles of the _____?
small rapidly moving muscles(eyes and digits), trunk and abdomen.
Skeletal muscle recovery occurs……
in reverse order with the diaphragm first
What is the NMB structure of succinylcholine?
2 molecules of acetylcholine linked by acetate methyl group(most resembles ACh)
Which NMB does this describe? Long, flexible, slender structure that binds to and activates cholinergic receptors?
Succinylcholine
Which NMB does this describe? Bulky and rigid molecules that contain acetylcholine structure but can’t bind to and activate cholinergic receptors?
Non-depolarizering agents
Which NMB are quaternary ammonium groups found?
all of them
Acetylcholine has a + charged quaternary ammonium group(4 carbons attached to a nitrogen) that……
attaches to negative charged cholinergic receptors
-90 mv resting membrane potential is painted by????
unequal distribution of K+ and Na+ ions across the cell membrane
NMJ contains 3 types of cholinergic nicotinic receptors what are they?
2 -are post-synaptic on skeletal muscle surfaces
(1 junctional and 1 extra junctional)
1 - is pre-synaptic on the nerve endings
What is the characteristic of TOF twitches in phase 1 NMB in a depolarizing block?
constant by diminished twitches
What is the characteristic of TOF twitches in phase 2 NMB in a depolarizing block?
twitches with fade
What is the characteristic of TOF twitches NMB using a non-depolarizing block?
fade
What is the characteristic of tetanus twitches in phase 1 of NMB in a depolarizing block?
constant but diminished
What is the characteristic of tetanus twitches in phase 2 of NMB in a depolarizing block?
fade
What is the characteristic of tetanus twitches NMB using a non-depolarizing block?
fade
What is the characteristic of post-tetanic potentiation twitches of a phase I depolarizing block?
NO TWITCHES(absent)
What is the characteristic of post-tetanic potentiation twitches of a phase 2 depolarizing block?
present
What is the characteristic of post-tetanic potentiation twitches of a non-depolarizer block?
present
Acetylcholine in the motor nerve endings is made by what and controlled by what?
made by acetylation of choline;controlled by the enzyme choline acetylase
Where is acetylcholine stored?
in the synaptic vesicles in motor nerve endings
How is acetylcholine released?
Released in synaptic cleft as packets or quanta-1000 molecules
What is the receptor acetylcholine binds to on the post-synaptic membrane
nicotinic receptors
In addition to binding acetylcholine, the 2 alpha units(alpha, beta, gamma, delta) are the sites of what?
sites of action for NMB drugs
Non-depolarsing NMB show preference for 1 of 2 alpha subunits
What is the result of occupation of the 1 of 2 alpha subunits by non-depolarizing NMB?
causes ion channel formed by receptors to remain closed
when we pretreat with a non-depolarizer(preventing fascinations)
-ion flow ends and depolarization can not occur
If 2 alpha subunits are occupied simultaneously, what happens?
ion channels opens and fasciculations occur
How much more is the epidural opioid dose more then the subarachnoid dose?
5-10 times more
