Cholinergic Antagonists

Flashcard maker : Jazzlyn Howe
Muscarinic Antagonists & Prototype
*Competitive Antagonists* at muscarinic receptors

Prototype: Atropine (SUPER IMPORTANT FOR BOARDS!)

Sources of Atropine/Related Compounds
Sources of Atropine/Related Compounds
Jimsom weed = related compound
Atropine – Structure, Mechanism, Common Contraindications
STRUCTURE: No fixed charge, crosses BBB
MECHANISM: Competitive antagonist at muscarinic receptors
CONTRAINDICATIONS: Men w/BPH, glaucoma patients

NOTE: Many drugs act as muscarinic antagonists and many drugs have atropine-like adverse effects. Overdoses of such drugs frequently produce effects that include those of atropine poisoning

Experiment: Effect of Competitive Antagonist (Atropine) on Agonist (ACh)
Experiment: Effect of Competitive Antagonist (Atropine) on Agonist (ACh)
A piece of intestine (smooth muscle) is sitting in a salt solution. When it contracts it pulls on something allowing the force of contraction to be measured.
*Parallel Shift to the Right = Competitive Agonist*
Experiment: Competitive Antagonist (Atropine) on Effects of Vagal Nerve Stimulation
Experiment: Competitive Antagonist (Atropine) on Effects of Vagal Nerve Stimulation
Stimulate Vagus nerve that travels to the piece of intestine to cause smooth muscle contraction.
Result:
1. Eventually your body runs out of ACh and there is none left to compete with the Antagonist.
2. Eventually the axons will become refractory (can only conduct so many APs so quickly)
Effects of Atropine due to Antagonism of Tonic ACh Activity (Blank Chart)
Effects of Atropine due to Antagonism of Tonic ACh Activity (Blank Chart)
Effects of Atropine due to Antagonism of Tonic ACh Activity (Filled In)
Effects of Atropine due to Antagonism of Tonic ACh Activity (Filled In)
What happens when Atropine is given at very low doses?
What happens when Atropine is given at very low doses?
Initially, Atropine will block Presynaptic Muscarinic Receptors, resulting in increased ACh release (due to lack of feedback inhibition). This will produce an initial Parasympathetic Effect, until Atropine levels are raised.

RESULT: May clinically observe slight bradycardia before heart rate increases as drug is being absorbed.

Relative Potency of Atropine to Cause Different Effects (Graph)
Relative Potency of Atropine to Cause Different Effects (Graph)
Most Prominent Atropine Effects Going from Low to High Dose
Most Prominent Atropine Effects Going from Low to High Dose
Above Line = common doses
Below Line = large doses
Scopolamine – Structure, Mechanism, Uses, “Other” Effects, Adverse Effects
STRUCTURE: Tertiary Amine
MECHANISM: Muscarinic Antagonist; greater CNS effects than Atropine
USES: *Motion* Sickness (Anti-Nausea Effects)
“OTHER” EFFECTS: Sedation, amnesia, dreamless sleep (no longer used for these now- there are better drugs)
ADVERSE EFFECTS: Dry mouth, drowsiness, blurred vision, dilation of pupils
Glycopyrrolate – Structure, Mechanism, Uses
STRUCTURE: Quaternary Amine
MECHANISM: Muscarinic Antagonist
USES: Various, often as pre-anesthetic agent (used to dry secretions in URT)
Ipratropium – Structure, Mechanism, Use
STRUCTURE: Quaternary Amine – can’t cross BBB
MECHANISM: Muscarinic Antagonist
USE: Inhalation to treat asthma
Benztropine – Mechanism, Use
MECHANISM: Muscarinic Antagonist
USE: Parkinson’s Disease; has a good ratio of CNS:peripheral effects
Tolterodine – Structure, Mechanism, Uses, Adverse Effects
STRUCTURE: Tertiary Amine
MECHANISM: Muscarinic Antagonist; somewhat selective for M3 receptors; blocks excessive stimulation of detrusor muscle
USES: Overactive bladder, urinary frequency, urgency, incontinence
ADVERSE EFFECTS: Dry mouth, constipation, blurred vision, etc.
Ophthalmologic Effects of Muscarinic Antagonists
Ophthalmologic Effects of Muscarinic Antagonists
By blocking tonic parasympathetic activity, antimuscarinic agents will cause mydriasis (dilation) and cycloplegia (inability to accommodate to see near)
Why can't atropine be given to patients with narrow-angle glaucoma?
Why can’t atropine be given to patients with narrow-angle glaucoma?
Because it would cause pupillary dilation, closing the Canal of Schlemm even more, blocking outflow of aqueous humor & increasing intraocular pressure.
Comparison of Muscarinic Antagonists After Topical Application to the Eye
Comparison of Muscarinic Antagonists After Topical Application to the Eye
Don’t think we have to know this. Check Patch
Dimenhydrinate
An Antihistamine that has prominent antimuscarinic activity and is used for *motion sickness*
Cardiovascular Uses of Muscarinic Antagonists
Used in MI to treat bradycardia secondary to excessive vagal activity

Rare patients with hyper-responsive vagal reflexes

Uses of Muscarinic Antagonists for GI Disorders
Peptic Ulcer (no longer used- better drugs now)
Diarrhea
Irritable bowel syndrome
“Anti-spasmodic”
Use of Muscarinic Antagonists to Treat Poisoning due to Muscarinic Agonist/Anticholinesterase
Need a tertiary amine, such as Atropine
May require “heroic” doses & repeated treatment

ONLY used for effects of ACh at *muscarinic* receptors (no effect at nicotinic receptors)

Atropine Poisoning
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter”

Dry mouth, skin, eyes, etc.
Blurred vision
Peripheral vasodilation
CNS effects cause confusion
Problems with thermoregulation; especially in infants & children hyperthermia may be prominent & lead to death

REMEMBER: Many drugs have, as a 2nd action, atropine-like effects. So the signs of intoxication for some of these drugs are the same as Atropine.

Nicotinic Antagonists – Generalizations and Subtypes
Most of the drugs are selective for either the nicotonic receptors at the NMJ or the autonomic ganglia.

All are quaternary and do not cross the BBB and are not well-absorbed from the GI tract

NMJ:
Competitive Antagonists
Depolarizing Blocker
AUTONOMIC GANGLIA:
Antagonist

Ganglionic Blocking Drugs – Selectivity, Prototype, Uses
SELECTIVITY: Selective for Nicotinic Nn receptors BUT they *block BOTH arms of the CNS*
PROTOTYPE: Hexamethonium
USES:
Formerly used for emergency treatment of hypertensive crisis (malignant hypertension)
*Main use is to understand ANS*
Effects of Ganglionic Blockade
Determined by the relative contribution of sympathetic & parasympathetic tone on various tissues at any given moment

HR increases because of predominant vagal control. However, both reflex tachycardia & reflex bradycardia will be absent since both sympathetic & parasympathetic arms of the ANS will be blocked.

GI tract will become non-active
Drop in peripheral vascular resistance (why? patch)

Dominant resting tone of Vasculature, HR, and GI Tract - Adrenergic or Cholinergic?
Dominant resting tone of Vasculature, HR, and GI Tract – Adrenergic or Cholinergic?
Competitive Antagonists at Nicotinic Receptors of the Skeletal NMJ – Prototype, Structure, Mechanism & “Reversal”
PROTOTYPE: Tubucurarine (Curare)
STRUCTURE: *All are quaternary & have no CNS effects*
MECHANISM:* Produces a non-depolarizing block*

Effect can be antagonized with nicotinic agonist, or by increasing the acetylcholine concentration (not used clinically) with an acetylcholinesterase inhibitor

Effect of a Competitive Antagonist on an ACh-Evoked Skeletal Muscle Contraction
Effect of a Competitive Antagonist on an ACh-Evoked Skeletal Muscle Contraction
Parallel shift to the Right – block can always be overcome with enough ACh
Effect of a Competitive Antagonist on Skeletal Muscle Contraction Evoked by Nerve Stimulation
Effect of a Competitive Antagonist on Skeletal Muscle Contraction Evoked by Nerve Stimulation
As stimulation increases, more & more motor units are recruited.

Eventually the ACh runs out

Tubocurarine – Absorption, Effects, Use, Elimination
ABSORPTION: It’s not absorbed from GI tract & doesn’t cross the BBB.
EFFECTS:
Rapid onset of action after IV injection, weakness progressing to flaccid paralysis
Small muscle involved in finely-controlled movements (e.g. eye muscles) are most sensitive. Large muscle are less sensitive & intercostal muscles & diaphragm are least sensitive.
USE: Paralysis for surgeries
ELIMINATION: Renal, Liver
Tubocurarine Limitations
Relatively long DOA (50 min, bad because you want it to stop after surgery)
Not completely selective; has some effect to inhibit transmission at autonomic ganglia
Can cause release of histamine from mast cells
Atracurium – Elimination, Duration of Action, Selectivity, Adverse Effect
ELIMINATION: Liver & spontaneous rxn (safer)
DURATION OF ACTION: Short (20-35 min)
[SELECTIVITY: No autonomic ganglia block, no effect at muscarinic receptors, Slight histamine release]
ADVERSE EFFECT: One product of spontaneous breakdown can cause seizures
Mivacurium – Elimination, Duration of Action, Selecitivty
ELIMINATION: *Plasma Esterase*
DURATION OF ACTION: *Very short* (10-20 min)
[SELECTIVITY: No autonomic ganglia block, no effect at muscarinic receptors, some histamine release]
Pancuronium – Elimination, Duration of Action, Selecitivty
ELIMINATION: Renal
DURATION OF ACTION: Moderate (>35 min)
[SELECTIVITY: No autonomic ganglia block, moderate muscarinic receptor antagonism, no histamine release]
Vecuronium – Elimination, Duration of Action, Selecitivty
ELIMINATION: Liver, renal
DURATION OF ACTION: Short (20-35 min)
SELECTIVITY: Most selective & most used clinically – no effects at other receptors
Succinylcholine – General Features
MECHANISM: *Depolarizing blocker of NMJ transmission*. It acts as an *agonist at nicotinic receptors of NMJ*. Unlike ACh, it is NOT a substrate for Acetylcholinesterase. It produces a *depolarizing block*

It has a*very rapid onset of action* and a *very brief duration of action*

It has NO CNS effects

Succinylcholine – Mechanism
Since it’s an agonist, onset of action is marked by fasciculations. These can be limited by giving a low dose of a curare-like drug first.

It produces depolarization block just like excess ACh. 2 phases:
I. Depolarization – Voltage gated Na⁺ channels locked in inactivated state
II. Desensitization – End plate is repolarized but insensitive to ACh

Succinylcholine – Adverse Effects
Lots of muscle contraction can result release of a lot of K⁺ into the bloodstream, causing *Hyperkalemia*.

*Malignant Hyperthermia*: rapid onset of extremely high fever with muscle rigidity, precipitated by exogenous agents in genetically susceptible individuals, especially by halothane or succinylcholine. (Medical Emergency)

Succinylcholine action is intensified by anticholinesterase drugs and can make the depolarizing block even “worse”

Experiment: Comparison of Curare & Succinylcholine Effects on Strength of Muscle Contraction
Experiment: Comparison of Curare & Succinylcholine Effects on Strength of Muscle Contraction
If more Tubocurarine was given, the strength of contraction could be brought down to 0.
Physostigmine (anticholinesterase agent) – Rapid and complete recovery of ACh transmission; ACh is able to accumulate and counteract the effects of curare.

Succinylcholine results in an initial increase in contraction, but it very quickly produces depolarization block. Physostigmine causes further loss of muscle contraction strength because ACh breakdown is blocked, so now there is ACh-mediated depolarization block on top of Succinylcholine-mediated depolarization block.

Succinylcholine – Pharmacokinetics***
Short duration of action is due to hydrolysis by *plasma cholinesterase* (pseudocholinesterase).
-In individuals with a genetically-determined abnormal plasma cholinesterase, succinylcholine has a much longer duration of action.
-Many mutations have been identified

*Psuedocholinesterase deficiency results in a delayed metabolism of succinylcholine* & mivacurium.

Heterozygous: slight prolongation of action
Homozygous: may last many hours

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