Term 1 Pharm - Cholinergic (Ach) Flashcards by ? ?

What is Acetylcholine (Ach) made of:

Acetate + ester bond + choline

Ach = Acetyl CoA + choline

How well did you know this?

Not at all

Perfectly

Enzyme that breaks dow ACh

acetylcholinesterase

How well did you know this?

Not at all

Perfectly

Once Ach is broken down what happens?

choline is recycled back into axon terminal and used to make more ACh

How well did you know this?

Not at all

Perfectly

All cholinergic receptors are activated by?

Ach

How well did you know this?

Not at all

Perfectly

What are the two categories of cholinergic receptors and where are they?

Subdivided into muscarinic or nicotinic

Muscarinic = Mostly located on parasympathetic effector cells, sweat glands of sympathetic post ganglions, endothelium

Nicotinic = Located in ganglia (Nn) and neuromuscular end plates (Nm)

How well did you know this?

Not at all

Perfectly

Where is acetylcholine (ACh) the neurotransmitter?

All autonomic ganglia
Postganglionic termini of parasympathetic fibers (post synaptic)
Postganglionic termini of sympathetic-cholinergic fibers (sweat glands) (post synaptic)
Adrenal medulla (specialized sympathetic ganglion)
Termini of somatic motor nerves to skeletal muscle, neuromuscular junctions (NMJ)/motor end plates
CNS

How well did you know this?

Not at all

Perfectly

Toxic Syndromes with too much cholinergic inhibition:

Anti-cholinergic
(Classic example = Atropine)

1) Mad as a hatter: delirium, MOST DANGEROUS TOXICTY IN ADULTS (self harm)
2) Blind as a bat: mydriasis, blurred vision, inhibits ciliary muscle constriction, makes closed angle glaucoma worse
3) Dry as a bone: reduces secretions, saliva, skin, eyes, and bronchial secretions
4) Hot as a hare: elevated body temperature, MOST DANGEROUS IN PEDIATRICS as resistant to usual antipyretics, have to use ice bath
5) Red as a beet: skin flushing
6) Also urinary retention from blocked detrusor, bronchodilation, constipation, tachycardia and hypertension

How well did you know this?

Not at all

Perfectly

Toxic Syndromes with too much cholinergic stimulation:

D	diarrhea
U	urination
M	miosis
B	bronchorrhea
B	bradycardia
E	Excitation of skeletal muscle leading to paralysis (nicotinic receptor), Emesis (muscarinic)
L	lacrimation
S	salivation
S	sweating

How well did you know this?

Not at all

Perfectly

Non-specific Direct Acting Cholinergic Agonist

Carbachol

How well did you know this?

Not at all

Perfectly

(3) Muscarinic direct acting cholinergic agonists

1) Bethanechol
2) Pilocarpine
3) Methacholine

How well did you know this?

Not at all

Perfectly

(3) Nicotinic direct acting cholinergic agonists

1) Varenicline
2) Nicotine
3) Succinylcholine

How well did you know this?

Not at all

Perfectly

Non-selective muscarinic and nicotinic receptor agonist

Actions: Used as an ocular agent it causes miosis and increases aqueous humor outflow.

Uses: Open angle glaucoma

Toxicity:
Overdose could cause effects similar to nerve gas (DUMBBELSS) but as a topical agent this is unlikely

Other facts: topical, not broken down efficiently by acetylcholinesterase, therefore long duration of activity

Carbachol (generic)

How well did you know this?

Not at all

Perfectly

Non-selective muscarinic receptor agonist

Actions: Used to increase detrusor muscle tone and GI motility post operatively

Uses: Urinary retention, neurogenic bladder, GERD

Toxicity:
reflex tachycardia (due to vasodilation), bronchoconstriction, increased secretory activity (sweat, GI/respiratory secretions)

Other facts: oral dosing

Bethanechol (generic)

How well did you know this?

Not at all

Perfectly

Non-selective muscarinic receptor agonist

Actions: muscarinic receptor activation

Indications: glaucoma, acute angle-closure, open angle glaucoma, decreases intraocular pressure and dry mouth/xerostomia, Sjogren syndrome-or head and neck cancer-associated,

Toxicity: reflex tachycardia (due to vasodilation), bronchoconstriction, increased secretory activity (sweat, GI/respiratory secretions)

Other facts: eye drops or oral

Pilocarpine (Salagen)

How well did you know this?

Not at all

Perfectly

Non-selective muscarinic agonist

Actions: Used to diagnose bronchial hypereactivity (asthma predominantly over COPD). “Methacholine challenge”, inhaled aerosolized methacholine with monitoring of bronchoconstriction

Uses: For diagnosis of asthma only

Other facts:
Inhaled only

Methacholine (Provocholine)

How well did you know this?

Not at all

Perfectly

Nicotinic cholinergic agonist

Actions: binds to nicotinic receptors; slower action than the nicotine found in cigarettes

Uses: smoking cessation; nicotine withdrawal

Adverse drug reactions: bronchospasm, nicotine dependence transference

Other facts: gum/patch/nasal

Nicotine (generic)

How well did you know this?

Not at all

Perfectly

Nicotinic receptor partial agonist

Actions: a partial agonist it reduces cravings for and decreases the pleasurable effects of cigarettes by inhibiting the ability of nicotine to stimulate the mesolimbic dopamine system

Uses: smoking cessation;
Adverse drug reactions: nausea, headache, insomnia, abnormal dreams

Other facts: oral

Varenicline (Chantix)

How well did you know this?

Not at all

Perfectly

Indirect acting cholinomimetic (presynaptic)

Has largely replaced bethanachol for post-surgery gastroparesis and antiemetic

Acts by stimulating presynaptic D2 receptors to trigger ACh release

Metoclopramide

How well did you know this?

Not at all

Perfectly

Indirect acting cholinomimetic
Cholinesterase inhibitor
Short acting (1)

Edrophonium

How well did you know this?

Not at all

Perfectly

Indirect acting cholinomimetic
Cholinesterase inhibitor
Intermediate acting (4)

1) Neostigmine
2) Pyridostigmine
3) Physostigmine
4) Donepezil, (galantamine, rivastigmine)

How well did you know this?

Not at all

Perfectly

Indirect acting cholinomimetic
Cholinesterase inhibitor
Long acting (3)

1) Echothiophate
2) Organophosphates (e.g. insecticides: parathion, malathion)
3) Nerve gases (e.g. Sarin, soman)

Reversible acetylcholinesterase inhibitor
Indirect cholinergic agonist

Actions: blocks action of acetylcholinesterase

Uses: Used to diagnose myasthenia gravis

Toxicity: cholinergic reaction (DUMBBELS)

Other facts: very short half-life 10-30 mins duration, iv, highly charged does not cross blood brain barrier

Edrophonium (Tensilon test)

Reversible cholinesterase inhibitor

Actions: increases acetylcholine availability for postsynaptic membrane receptors

Uses: Myasthenia gravis, nondepolarizing neuromuscular blockade reversal (rocuronium and vecuronium), urinary retention

Toxicity: cholinergic reaction (DUMBBELSS)

Other facts: iv/im/sc does NOT enter CNS

Neostigmine (Bloxiverz)

Reversible cholinesterase inhibitor

Actions: indirectly stimulates both nicotinic and muscarinic acetylcholine receptors

Indications: glaucoma, Alzheimer’s disease, delayed gastric emptying, anticholinergic toxicity with CNS effects e.g. atropine overdose, nondepolarizing neuromuscular blockade reversal

Toxicity: cholinergic reaction (DUMBBELSS)

Other facts: crosses the BBB so not used for myasthenia gravis (uncharged and lipid soluble), iv/im

Physostigmine (generic)

Reversible cholinesterase inhibitor Actions: indirectly stimulates both nicotinic and muscarinic acetylcholine receptors Indications: myasthenia gravis treatment, shorter half-life than neostigmine Toxicity: cholinergic reaction (DUMBBELS) Other facts: does not cross blood brain barrier, low oral bioavailability,

Pyridostigmine (generic)

Reversible cholinesterase inhibitor Actions: indirectly stimulates both nicotinic and muscarinic acetylcholine receptors Indications: Alzheimer’s associated dementia Toxicity: GI upset Other facts: crosses blood brain barrier, 100% oral bioavailability,

Donepezil (Aricept) Other drugs used for dementia: - Rivastigmine (Exelon) reversible cholinesterase inhibitor patch form reduces GI upset - Galantamine NN agonist and acetylcholinesterase inhibitor

IRreversible cholinesterase inhibitor Actions: binds irreversibly to acetylcholine binding site on cholinesterases (cholinesterase inhibitor) Indications: glaucoma topical Toxicity: lacrimation, stinging Other facts: topical only, very long half-life

Echothiophate (Phospholine Iodide)

the ONLY Indirect Cholinergic Antagonist = Anticholinergic (muscarinic and nicotinic)

Botulism toxin (BOTOX) - Botulinum toxin type A, Produced from Clostridium botulinus → botulism - Most toxic molecule known, large molecule - Inhibits release of ACh from synaptic vesicles - Blocks docking of vesicles and neurotransmitter release

Anticholinergic = Parasypatholytic Muscarinic Receptor Antagonists (prototype)

Atropine

Clinical uses of muscarinic anticholinergics

- Motion sickness - Irritable bowel syndrome - Urinary urgency and bladder spasm - Ophthalmology (dilating pupil) - Parkinson’s disease - Bronchodilation in asthma and COPD - Cholinergic poisoning

Muscarinic anticholinergic for Motion sickness:

Scopolamine

Muscarinic anticholinergic for Irritable bowel syndrome

Dicyclomine

Muscarinic anticholinergic for Urinary urgency and bladder spasms

Oxybutynin and Glycopyrrolate

Muscarinic anticholinergic for Ophthalmology, dilating pupil

Tropicamide (shorter duration of action than atropine)

Muscarinic anticholinergic for Parkinson’s disease

Benztropine

Muscarinic anticholinergic for Bronchodilation in asthma and COPD

Ipratropium and tiotropium

Muscarinic anticholinergic for Cholinergic poisoning

Atropine and 2-PAM

Non-selective muscarinic receptor blocker Actions: prevents action of acetylcholine, lowers activity of all muscles and glands regulated by the parasympathetic nervous system Uses: organophosphate poisoning (insecticide, nerve gas –given with Pralidoxime/2-PAM), optically for pupil dilation, bradycardia, to reduce secretions Toxicity: (Toxic Syndromes with too much cholinergic inhibition) Other facts: SC; IM; IV; INJ lipid soluble so crosses BBB for when toxins have also crossed BBB

Atropine

Reactivates cholinesterase Actions: binds to organophosphate inactivated acetylcholinesterase and accelerates reactivation Uses: cholinesterase inhibitor overdose, organophosphate insecticide poisoning, organophosphate nerve agent poisoning Toxicity: when used with atropine, as it usually is, atropine toxicity is enhanced (Toxic Syndromes with too much cholinergic inhibition) Other facts: iv/im only, useful if administered soon after exposure to toxin, military has stockpiles of auto-injectors in case of nerve gas use

Pralidoxime (2-PAM)

Muscarinic (some M1 specificity) and histamine receptor blocker Actions: centrally acting anticholinergic/antihistamine agent Uses: parkinsonism, dystonia, extrapyrimidal symptoms Toxicity: (similar to atropine) Other facts: IM IV

Benztropine (Cogentin)

Non-selective muscarinic receptor blocker Actions: Some indication of M1 receptor specificity, anti-emetic (vomit) Uses: motion sickness, to dilate eye Toxicity: (similar to atropine) Other facts: transdermal, can cross BBB,

Scopolamine (Scopoderm)

Muscarinic receptor blocker, anticholinergic Actions: inhaled bronchodilator (M3 receptors in lung) Uses: asthma and COPD. Toxicity: rare and only through overdosing, dry mouth and sedation, other atropine-like anticholinergic effects Other facts: inhaled, bad taste, slower onset than beta-2 agonists (albuterol, etc.) can be combined with albuterol in 1 inhaler; duration 6-8 hrs.;

Ipratropium bromide (Atrovent HFA) Tiotropium (Spiriva) longer acting used more for COPD.

Non-selective muscarinic receptor blocker Actions: relaxes smooth muscle, inhibits bradykinin- and histamine-induced bowel spasms Uses: irritable bowel syndrome Toxicity: similar to atropine, dry mouth, nausea, most common and at higher doses deliriant effects Other facts: oral

Dicyclomine (Bentyl)

What is the ONE depolarizing NM antagonist (NMJ blocker)? Explain how it works?

Succinylcholine - Initial activation → subsequent deactivation - Initial depolarization leads to muscle fasciculations - Prolonged receptor occupancy with ACh leads to receptor phosphorylation and inactivation (termed: depolarization-desensitization blockade) - Result is a paradoxical flaccid paralysis which cannot be practically reversed; have to wait until agonist is cleared - Over activation of the nicotinic receptor produces a net K+ efflux from muscle → hyperkalemia

Nicotinic NMJ blocker (depolarizing), Neuromuscular Blockers, nicotinic acetylcholine receptor agonist Actions: production of complete skeletal muscle relaxation, flaccid paralysis, Initial stimulation of nicotinic receptors is not terminated and the motor endplate depolarizes, which causes flaccid skeletal muscle paralysis; is not broken down by acetylcholinesterases Uses: short-term muscle relaxation in anesthesia and intensive care, intubation Toxicity: BLACK BOX rare acute rhabdomyolysis w/ hyperkalemia followed by ventricular dysrhythmias, cardiac arrest, and death after admin. to apparently healthy children subsequently found to have undiagnosed skeletal muscle myopathy, most frequently Duchene muscular dystrophy; Other facts: IV, short acting , ONLY NMJ depolarizing blocker in clinical use; do NOT give to patients lacking ChE (causes prolonged paralysis), no reversal agent

Succinylcholine (Anectine)

Nicotinic NMJ blocker (non-depolarizing), Reversible competitive inhibition *Prototypic nondepolarizing blocker Actions: directly blocks receptors on nicotinic end plate, thereby causing flaccid skeletal muscle paralysis Uses: production of complete skeletal muscle relaxation (surgery, etc), first of its class now replaced by safer alternatives (cisatracurium and rocuronium) Toxicity: respiratory failure, produces paralysis in fully conscious patients, tachycardia, hypertension, histamine release, ganglionic and muscarinic side effects Other facts; duration of action 30-60 minutes, neostigmine will reverse action, Quaternary amine so minimal CNS effects

d-Tubocurarine (curare) - 15th century Europeans met Amazonian Indians hunted with arrows dipped in curare extract - can eat prey b/c not orally bioavailable - Produces paralysis in fully conscious patients - Never give such a drug to an unanesthetized patient - Never let a patient emerge from anesthesia before reversing the paralysis

Nicotinic NMJ blocker (non-depolarizing), Reversible competitive inhibition, aminosteroid Uses: directly blocks receptors on nicotinic end plate, thereby causing flaccid skeletal muscle paralysis, used in drug cocktail for executions Uses: production of complete skeletal muscle relaxation (surgery, etc.), Toxicity: BLACK BOX admin. by adequately trained individuals familiar w/ actions, characteristics, and hazards. respiratory failure, produces paralysis in fully conscious patients, tachycardia, hypertension, histamine release, ganglionic and muscarinic side effects Other facts; duration of action 30-60 minutes, neostigmine will reverse action, hepatic impairment: caution advised

Vecuronium (generic)

Nicotinic NMJ blocker (non-depolarizing), Reversible competitive inhibition, Benzoisoquinolinium analogue Actions: antagonizes motor endplate acetylcholine receptors Uses: production of complete skeletal muscle relaxation (surgery, etc.), intubation Toxicity: respiratory failure, produces paralysis in fully conscious patients, tachycardia, hypertension, histamine release, ganglionic and muscarinic side effects Other facts; duration of action 30-60 minutes, neostigmine will reverse action

Cisatracurium (Nimbex)

For nondepolarizing nicotinic blockers (competitive inhibitors) you reverse with:

Neostygmine (do not need CNS penetration)

How do you reverse depolarizing nicotinic blockers (succinylcholine)?

There is no reversal agent only time will allow breakdown of succinylcholine by cholinesterases

Nicotinic ganglionic blocker (non-depolarizing), Reversible competitive inhibition, Actions: blocks both the sympathetic nervous system and the parasympathetic nervous system. It acts as a non-depolarizing competitive antagonist at the nicotinic acetylcholine receptor Uses: rarely used but sometimes for hypertensive crisis or in dissecting an aortic aneurism Toxicity: Very toxic and only used in emergency situations, Orthostatic hypotension, urinary retention, constipation, impaired accommodation of lens of the eye Other facts; short-acting, IV, does not cross BBB

Trimetaphan (Arfonad)

Bacterial exotoxin, inhibitor of ACh release from nerve terminals Actions: causes botulism; interferes with docking proteins on the interior of the nerve membrane (vesicles containing ACh cannot dock properly and therefore cannot release Ach) Uses: remove facial wrinkles and prevent hyperhydrosis (BoTox), migraines Toxicity: BLACK BOX Distant Spread of Toxin Effect can produce sx consistent w/ botulinum toxin: asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties; swallowing and breathing difficulties may be life-threatening and deaths reported; sx occur hours to weeks after injection; Other facts: Local injections to prevent systemic effects

Botulinum toxin (BoTox)