Neuromuscular and ganglionic blockers Flashcards
Definition of Ganglionic Blockers (GBs)?
nicotinic receptor antagonists
What do GBs do?
block reflexes- baroreceptor, pupillary
Examples of GBs…
Trimethaphan-hypotension for surgery
Mecamylamine-in severe hypertension, smoking cessation, Tourette’s Syndrome
Natural state of vascular smooth muscle tone in body
Sympathetic > Parasympathetic
blockade=vasodilation
Natural state of all other ANS function
Parasympathetic > Sympathetic
blockade=tachycardia
What are the two ways to block Ach transmission?
pre-synaptic: decrease Ach formation or release, increase metabolism
post-synaptic: block cholinergic receptors
Which one is the clinical use?
block cholinergic receptors
limitation of neuromuscular blockers?
quarternary ammonium->only peripheral use
What is the function of neuromuscular blockers?
to relax skeletal muscles needed in:
surgery, orthopedic procedures, bronchoscopy, artificial respiration/intubation
First clinically used neuromuscular blockers?
curare: D-tubocurarine is the major active alkaloid in it
What is the purpose of neuromuscular blockers?
allow for using different classes of drugs for muscle relaxation and anesthesia
Train of Four (TOF)?
used to monitor the strength of neuromuscular blockage
TOF ratio can be used for…
determine at the end of procedure if the patient can be extubated
When extubation can occur?
TOF ration >0.7
What is non-depolarizing blocking agent?
competitively blocking the binding of ACh to its receptors
What is depolarizing blocking agent?
depolarizing the sarcolemma of the skeletal muscle fiber-> persistent depolarization makes the muscle fiber resistant to further stimulation by ACh
Non-depolarizing vs. depolarizing agent
“Fade” vs. no “Fade” until TOF ratio
What determines if the patient’s muscles are sufficiently blocked?
the number of twitches: procedures are performed when patient responds with 1-2 twitches
under this condition, blockade can be quickly reversed
Sequence of muscle paralysis under neuromuscular blockers?
muscles of eye, speech, then fingers, toes, limbs, lastly intercostals and diaphragm
Sequence of muscle paralysis mimics…
Guillain-Barre syndrome
Example of depolarizing agent (nicotinic Ach receptor agonist)
Succinylcholine
Characteristics of Succinylcholine
short duration=5-10mins
metabolized by butyrylcholinesterase to choline, which incases BP
Benefits of using Succinylcholine
fast onset, short duration of action
When do you use Succinylcholine?
trauma care, INTUBATION, electro-convulsant therapy
When not to use Succinylcholine?
patients with HYPERKALEMIA -cause cardiac arrest
Examples of non-depolarizing agents (curare-like, nicotinic Ach receptor antagonist)
Pancuronium (180mins)
Vecuronium, Atracurium (30-40mins)
Trimethaphan (short)
all easily reversible->widely used
mechanism of Succinylcholine?
nicotinic Ach receptor agonist->persistant opening of Na+ channel->prevent repolarization->no further action potentials occurs
What is Rocuronium?
non-depolarizing neuromuscular blocker (muscle relaxant)
There are two ways to reverse Rocuronium actions.
use AchE inhibitor like Neostigmine
use Sugammadex- sequester Rocuronium by directly binding to it
The function of AchE inhibitors is like…
a cholinergic agonist
its function relies on the presence of Ach-> so little effect on function of M3 receptors in blood vessels as no Ach in blood stream anyway
Two types of cholineesterases
AchE in synapses w/. high affinity for Ach
BuchE in plasma, metabolize Succinylcholine and procaine
3 classes of AchE inhibitors
Carbamates
Organophosphates
Quaternary ammonium alcohols
How Carbamates work?
temporarily covalent bound to AchE
reversible, dissociate in 0.5-8hrs
1st example of Carbamates
Physostigmine:
tertiary amine, enters CNS
for atropine overdose
Clinical: glaucoma, Alzheimer’s Disease
2nd and 3rd examples of Carbamates
Neostigmine and Pyridostygmine
quartanary amine, peripherally restricted
reveal of NMB, post-operative ileus, bladder distention
Pyrido=less side effect, longer duration
Clinical: Myasthenia gravis
How Organophosphates work?
irreversibly covalent bound to AchE -> long duration of action
Clinical: glaucoma- not commonly used
What other uses of Organophosphates?
as insecticides and nerve gas (sarin)
What is Pralindoxime?
antidote for pesticide or never gas (AchE inhibitors) poisoning
When to give Pralindoxime?
it is only effective within a few hours of exposure to insecticides
What is Organophosphate Aging?
once organophosphate covalently bound to AchE, the bond will be hydrolyzed and this step is IRREVERSIBLE, called aging.
Mnemonics for symptoms of AchE inhibitor poisoning is…
D=diarrhea(M3) U=urination(M3) M=miosis(M3) B=bronchospasm(M3) B=bradycardia(M2) E=excitation of skeletal muscles and CNS(Nm) L=lacrimation(M3) S=sweating(M3) S=salivation(M3)
The trigger word for AchE inhibitor poisoning is…
farmer
How quaternary ammonium alcohol work?
binds non-covalently, reversible
Example of quaternary ammonium alcohol
Edrophonium:
short action(5-10mins)
Clinical: used for diagnosis of Myasthenia Gravis(MG) and to distinguish it from Lambert Eaton MG
Clinical effect of Edrophonium in MG
MG patient exercise-> worsen muscle strength-> give Edrophonium-> improves muscle strength
What is Lamber Eaton MG?
Abs against calcium channels rather than Abs against Nm in MG
Clinical effect of Edrophonium in Lamber Eaton MG
Lamber Eaton MG patient exercise-> improves muscle strength-> give Edrophonium-> no effect
What is cholinergic crisis?
overdose of AchE inhibitors-> overstimulation-> paralysis-> weak muscles
How to distinguish MG from cholinergic crisis?
Edrophonium-> no effect in CC
-> improves muscle strength in MG
Contraindications to use of parasympathomimetic drugs:
Asthma and COPD Coronary deficiency Peptic ulcer->increase acid secretion Obstruction of urinary or GI tract Epilepsy
Cholinergic and adrenergic centers in CNS
brain stem and nucleus basal is of Meynert ->Ach
locus coeruleus -> NE
Alzheimer Disease
loss of cholinergic neurons in brain due to improper processing of beta-amyloid proteins->toxicity->apoptosis of neurons
AchE inhibitors in Alzheimer disease
Donepezil, Rivastigmine (carbmate), Galanthamine (from daffodil):
reversible binding to AchE
enhance cognitive ability
lose effect as Ach decreases due to Ach-producing neurons die
DO NOT slow progression of AD
How to increase Galanthamine bioavailability?
give inhibitors of CYP3A4, CYP2D6
