5 - Cholinergic Drugs Flashcards
Botulinum Toxin is how many more times as deadly when compared to Cyanide?
200,000,000
Botulinum Toxin Pathophys
Targets Cholinergic System (all Cholinergic synapses, not just NMJ)
Binds to protein found in presynaptic cholinergic terminal plasma membrane
Gets taken up into the cytoplasm
Cleaves an enzyme essential for the exocytosis of ACh
Careful! Don’t let it get to the diaphragm!
Wears off, so if you want extended effect, repeated injections are required
Uses of Botulinum Toxin
Paralyze skeletal muscle (e.g. blepharospasm, hemifacial spasm, strabismus, focal dystonia, wrinkles) Stroke paralysis Migraine headaches Facial tics Stuttering Lower back pain Incontinence Writer's Ccramp Carpal tunnel syndrome Tennis elbow Spasmodic dysphonia Experimental treatments (morbid obesity, ulcer prevention, vaginal spasms, newborns with club feet, excessive sweating, overactive bladder)
Blepharospasm
An involuntary closure of the eyelids.
Treat with botulinum toxin
Hemifacial Spasm (HFS)
Involuntary twitching of the facial muscles on one side of the face.
Treat with multiple injections of botulinum toxin
Strabismus
Lazy eye
Eyes are misaligned
Inject botulinum toxin into one or more of the extraocular muscles to weaken them
Dystonia
Disorder of posture
Focal Dystonia
A confined disorder of posture. Treat with botulinum toxin and deep tissue massage to ease the spasms.
Anticholinesterases
Block Acetyl Cholinesterase, prolongs the effect of ACh, facilitates nerve transmission in both Muscarinic and Nicotinic synapses.
How is ACh’s action in the synaptic cleft normally terminated?
Hydrolysis via Acetyl Cholinesterase
How do Anticholinesterases behave differently at nicotinic synapses, when compared to their action at muscarinic synapses?
At nicotinic synapses, a sufficiently long-lasting Anticholinesterase has a biphasic effect: Initial facilitation of transmission, followed by receptor desensitization/blockade.
Mechanism of Acetylcholinesterases
ACh binds to the Esteratic Site of the Active Center of Acetylcholinesterase, and is cleaved to Acetic Acid, while the rest covalently bonds to the Acetylcholinesterase
Mechanism of the 3 types of Anticholinesterases
Anticholinesterase binds competitively to Esteratic Site of Active Center of Acetylcholinesterase
3 Types of Anticholinesterases
Truly Reversible Anticholinesterases (Short-Acting) Reversible Carbamates (Long-Acting) Organophosphorous Anticholinesterases (Irreversible)
Truly Reversible Anitcholinesterases
Binds weakly, falls off easily, short-acting
Reversible Carbamates
Has similar molecular structure to ACh, is hydrolyzed in much the same mechanism, but takes much longer than ACh does. Longer-acting. e.g. Neostigmine
Neostigmine
Reversible Carbamate (Anticholinesterase), competitively binds to Acetylcholinesterase
Organophosphorus Anticholinesterases
Irreversible. Phosphorus covalently bonds to Esteratic Site, ruining it for any ACh in the future.
Lipid-soluble. Crosses skin, lungs readily. Enters bloodstream readily. Crosses Blood-Brain Barrier readily.
Why does Sarin cause diaphragmatic paralysis?
Sarin, an Organophosphorus Anticholinesterase, has a bi-phasic effect on the nicotinic synapses of the phrenic nerve. After spasm, we see blockade.
How do you treat acute Organophosphorus Anticholinesterase poisoning?
3 drugs in concert:
Atropine (competitive muscarinic antagonist)
Benzodiazepines (to suppress seizures)
Pralidoxime
Atropine
Competitive Muscarinic Antagonist. High doses penetrate CNS
Benzodiazepines
Diazepam
Blocks seizures
Pralidoxime
Treats Organophosphorous Anticholinesterase poisoning. The phosphorous has a higher affinity for the Pralidoxime’s oxygen, than for the Acetyl Cholinesterase Esteratic Site’s oxygen
What must be kept in mind when administering Pralidoxime?
Do it quickly. After about 1 hour, the phosphorylated enzyme “ages” and becomes impervious to Pralidoxime.
Pralidoxime also only works peripherally. It does not penetrate CNS.
Myasthenia Gravis
Autoimmune disease. Body makes Ab against NMJ nicotinic receptor, leads to muscle weakness and fatigue.
Treat with immunotherapy OR use Neostigmine, Pyridostigmine, or other Reversible Carbamate
How do the Reversible Carbamates (e.g. Neostigmine, Pyridostigmine) treat Myasthenia Gravis?
ACh’s effect is prolonged, getting more efficient use of the the muscarinic receptors you have left at the NMJ.
Why must we titrate Reversible Carbamates very carefully when using them to treat Myasthenia Gravis?
We want to avoid the bi-phasic effect of Anticholinesterases. We titrate until we see blockade (also known as cholinergic crisis), then dial it back a little.
Alzheimer’s Disease
Widespread loss of synapses and neurons throughout the brain. Causes dementia.
Early stages - Nucleus Basalis of Meynert.
One of the only treatments is Anticholinesterases, getting the most efficient use of the cholinergic synapses you have left. Specifically Truly Reversible (but the longer-lasting end of that spectrum).
Donepezil
Donepezil
Truly Reversible Anticholinesterase, though at the longer-lasting end of that classfication
Used for Alzheimer’s treatment
2 Classes of Nicotinic Blocking Drugs
Competitive/Stabilizing Blockers
Depolarizing Blockers
Competitive/Stabilizing Nicotinic Blockers
D-Tubocurarine
Large, multi-ringed, inflexible, has positively-charged Ns at opposite ends of the molecule
Competitive antagonist.
Metocurine is methylated version that is more potent
What sort or receptors predominate autonomic ganglia?
Nicotinic receptors
D-Tubocurarine
Metocurine
Competitive Nictonic Blockers that act at both NMJ and Autonomic Ganglia
Arterioles - Dominant Input at Rest
Sympathetic (adrenergic)
Veins - Dominant Input at Rest
Sympathetic (adrenergic)
Heart - Dominant Input at Rest
Parasympathetic (cholinergic)
Iris - Dominant Input at Rest
Parasympathetic (cholinergic)
Ciliary Muscle - Dominant Input at Rest
Parasympathetic (cholinergic)
GI Tract - Dominant Input at Rest
Parasympathetic (cholinergic)
Urinary Bladder - Dominant Input at Rest
Parasympathetic (cholinergic)
Salivary Glands - Dominant Input at Rest
Parasympathetic (cholinergic)
Sweat Glands - Dominant Input at Rest
Sympathetic (cholinergic)
Arterioles - Effect of Ganglionic Blockade
Vasodilatation
Increased peripheral flow
Hypotension
Veins - Effect of Ganglionic Blockade
Dilatation
Pooling of blood
Decreased venous return
Decreased cardiac output
Heart - Effect of Ganglionic Blockade
Tachycardia
Iris - Effect of Ganglionic Blockade
Mydriasis
Ciliary Muscle - Effect of Ganglionic Blockade
Cycloplegia
GI Tract - Effect of Ganglionic Blockade
Reduced tone and motility, constipation
Urinary Bladder - Effect of Ganglionic Blockade
Urinary retention
Salivary Glands - Effect of Ganglionic Blockade
Xerostemia
Sweat Glands - Effect of Ganglionic Blockade
Anhidrosis
Depolarizing Nicotinic Blockers
Weak nicotinic agonists that induce a low level of depolarization
Succinylcholine
Succinylcholine
Bi-phasic effect: Binds like ACh, causes initial increase in transmission, then desensitization/blockade.
What do you see differently when you administer a Depolarizing Nicotinic Blocker, when compared to a Competitive/Stabilizing Nicotinic Blocker
Competitive (Antagonist): Paralysis
Depolarizing (Agonist): Twitch, then paralysis
Pancuronium
Competitive Nicotinic Blocker
Steroid derivative
Similar structure to D-Tubocurarine
Acts in the same mechanism
What Nicotinic Blocker would you use for a tracheal intubation?
Succinylcholine
Fast Onset
Short Duration
Atracurium - Origins, Onset, Duration, Side Effects
Derivative of Tubocurarine
Onset: 2 - 4 min
Duration: 30 - 60 min
Side Effects: Milder Histamine Release
Vecuronium - Origins, Onset, Duration, Side Effects
Derivative of Pancuronium
Onset: 2 - 4 min
Duration: 60 - 90 min
Side Effects: No Vagal Side Effects (yay!)
Mivacurium - Origins, Onset, Duration, Side Effects
Derivative of Atracurium
Onset: 2 - 4 min
Duration: 12 - 18 min
Side Effects: Milder Histamine Release
Rocuronium - Origins, Onset, Duration, Side Effects
Derivative of Vecuronium
Onset: 1 - 2 min
Duration: 30 - 60 min
Side Effects: No Vagal Side Effects (yay!)
Genealogy of Tubocurarine derivatives
Tubocurarine
Onset: 4 - 6
Duration: 80 - 120
Side Effects: Histamine Release
Atracurium
Onset: 2 - 4
Duration: 30 - 60
Side Effects: Milder Histamine Release
Mivacurium
Onset: 2 - 4
Duration: 12 - 18
Side Effects: Milder Histamine Release
Genealogy of Pancuronium derivatives
Pancuronium
Onset: 4 - 6
Duration: 120 - 180
Side Effects: Inhibits Vagal effect on the heart
Vecuronium
Onset: 2 - 4
Duration: 60 - 90
Side Effects: No Vagal Side Effects (yay!)
Rocuronium
Onset: 1 - 2
Duration: 30 - 60
Side Effects: No Vagal Side Effects (yay!)
Succinylcholine - Onset, Duration, Side Effects
Onset: 1 - 2 min
Duration: 5 - 8 min
Side Effects: Fasciculation
Tubocurarine - Onset, Duration, Side Effects
Onset: 4 - 6 min
Duration: 80 - 120 min
Side Effects: Histamine Release
Pancuronium - Onset, Duration, Side Effects
Onset: 4 - 6 min
Duration: 120 - 180 min
Side Effects: Inhibits Vagus input to Heart
