Category:

Indirect cholinergic antagonist

*Can affect ganglion too!!!

*Remember it also inhibits ACh action on skeletal muscle too!

Mechanism:

Botulinum toxins are enzymes that cleave nerve terminal proteins (synaptobrevin and others) blocking ACh-containing vessicle fusion & release from cholinergic terminals.

Clinical Uses:

Muscle spasm, smooth wrinkles, and reduction of excessive sweating

Category:

Cholinergic indirect antagonist

*Can affect ganglion too!

Mechanims:

Blocks reuptake of choline from synaptic cleft by high affinity choline-transporter into nerve terminal

Uses:

Mostly in vitro experimentation, no clinical use.

Pneumonic:

HEMIcholinium-3 = 3 HEMIS smash the nerve terminal transporter

Category:

Indirect cholinergic agonist

Mechanism:

Allosteric acetylcholinesterase inhibitor

Clinical Use:

Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease

Pneumonic:

DONepezil = DON't I know you? (Alzheimer patients lose memory)

ALLzheimer = ALLosteric AChE inhibitor

Category:

Indirect cholinergic agonist

Mechanism:

Organophosphate AChE inhibitor, thus increasing endogenous ACh

Clinical application:

Glaucoma by increasing endogenous ACh

Isofluorophate^(C)

(Fluostigmine, DFP)

Category:

Indirect cholinergic agonist

Mechanism:

Organophosphate AChE inhibitor

Clinical Use:

1. Opthamology: used as a miotic (pupil constricting) agent to treat mydriasis

Category:

Indirect cholinergic agonist

Mechanims:

Reversibly binds AChE and acts as competitive inhibitor, thus increasing endogenous ACh

Clinical Uses:

1. Reversal of neuromuscular block by non-depolarizing drugs

2. Diagnosis of myasthenia gravis (very short-acting)

- In differentiating myasthenic crisis and cholinergic crisis, endrophonium will improve muscle strength in myasthenic crisis, but decrease it in cholinergic crisis.

Category:

Indirect cholinergic agonist

Mechanism:

Quaternary (4^o) ammonium carbamate ester AChE inhibitor, thus increasing endogenous ACh.

*4^o is always charged --> no passage through BBB --> NO CNS involvement

Clinical Use:

1. Reversal of NMJ block (post operative)

2. Treatment of myasthenia gravis

3. Post-operative and neurogenic ileus and urinary retention

Pneumonic:

NeOstigmine CNS = NO CNS penetration

Category:

Indirect cholinergic agonist

Mechanism:

Tertiary (3^o) ammonium carbamate ester AChE inhibitor, thus increasing endogenous ACh --> can cross BBB (when not charged) --> CNS

Clinical Use:

1. Reversal of severe atropine poisoning (IV);

2. Occasionally used in acute glaucoma (topical) as it increases outflow in aqueous humor

Pneumonic:

ph'YS'ostigmine = EYES --> CNS

Helps recover from the "phys"ical effects of atropine poisoningQ

Pralidoxime^(C)

(2-PAM)

Category:

Reactivator of organophosphate-inhibited AChE

Mechanism:

Oxime compound displaces organophosphate from inhibited AChE. Time dependent --> if too long it does not work.

Clinical Use:

Reversal of organophosphate poisoning or AChE inhibitor poisoning.

Category:

Cholinergic indirect antagonist

*Can affect ganglion too!

Mechanism:

Inhibits vessicle associated transporter (VAT), which is required for packaging ACh into vessicles in pre-synaptic nerve terminal.

Clinical Use:

Experimental drug, not used clinically

Category:

Indirect cholinergic agonist

Mechanism:

Quaternary (4^o) ammonium carbamate ester AChE inhibitor, thus increasing endogenous ACh

*Does not penetrate CNS (4^o) and is LONG lasting

Clinical Use:

Treatment of myesthenia gravis (long lasting), thus increases muscle strength

Pneumonic:

Last so long, that even with myesthenia gravis you can "PYRR"ade (parade) all day!

Category:

Direct nicotinic & muscarinic cholinergic agonist

Mechanism:

Duh

Clinical Use:

Cataract and other eye surgeries to constrict the pupil.

Carbachol and Acetylcholine are 4^o amines that are always charged and cannot enter CNS.

Decamethonium^(C)

(C10)

Category:

Partial nicotinic (N_M) agonist

Mechanism:

Upond binding AChR, it causes depolarization, thus acting as neuromuscular blocker. It is not degraded, thus muscle is maintained in depolarized state.

Clinical Use:

Used in the past to induce paralysis in patients

Pneumonic:

DECK-a-METH-onium = you wouldn't have to "deck" a crazy "meth" addict if you give them this drug!

Category:

Partial nicotinic (N_M) agonist

Mechanism:

Binds AChR causing depolarization and impeding action of ACh, resulting in neuromuscular relaxation and paralysis.

Clinical Use:

Used to facilitate intubation. It is degraded by a plasma cholinesterase butyrylcholinesterase.

Possible side effects include hyperkalemia, malignant hyperthermia and death.

Category:

Competitive nicotinic (N_M) antagonist

Mechanism:

Non-depolarizing competitive antagonist of AChR --> prevents ACh from binding receptor, which results in neuromuscular relaxation.

Clinical Use:

Used in the past as a skeletal muscle relaxant to facilitate intubation, surgical procedures or mechanical ventilation.

Relatively short acting as it is rapidly metabolized by plasma cholinesterase enzymes.

Tubocurarine chloride^(B/C)

(d-tubocurarine)

Category:

Competitive nicotinic (N_M) antagonist

Mechanism:

Non-depolarizing competitive antagonist of AChR --> prevents ACh from binding receptor, which results in neuromuscular relaxation.

Clinical Use:

Used in the past a skeletal muscle relaxant to facilitate intubation, surgical procedures or mechanical ventilation.

Relatively LONG duration. Rarely used anymore as it causes histamine release. Also a ganglion blocking agent that results in hypotension.

Category:

Ryanodine receptor antagonist

Mechanism:

Binds to RyR and inhibits Ca²⁺ induced Ca²⁺ release, resulting in muscular relaxation

Clinical Use:

The only specific and effective treatment for succinyl choline induced malignant hyperthermia

Dimethylphenyl piperazinium^(C)

(DMPP)

Category:

Ganglionic nicotinic (N_G) agonist

Mechanism:

Binds to autonomic ganglia nicotinic receptors and activates them

Clinical Use:

Only used experimentally

Category:

Ganglionic nicotinic (N_G) agonist and neuromuscular nictonic (N_M) agonist

Mechanism:

Binds to nicotinic receptors and activates them

Clinical Use:

Smoking cessation

Category:

Ganglionic nicotinic (N_G) antagonist

Mechanism:

Binds to nicotinic ganglia receptors, blocking activation. This blocks sympathetic and parasympathetic nervous systems.

Clinical Use:

1. Smoking cessation

2. Used experimentally to prevent vagal response to changes in blood pressure (e.g. reflex bradycardia caused by NE)

Toxicity:

Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction

Pneumonic:

Put a HEX on smokers to help the quit!

Smoking cessation

Category:

Ganglionic nicotinic (N_G) antagonist

Mechanism:

Binds to nicotinic ganglia receptors, blocking activation. Non-depolarizing competitive antagonist --> blocks both sympathetic and parasympathetic nervous systems.

Clinical Use:

1. Previously used to treat malignant hyoertension and produce controlled hypotension.

Category:

Muscarinic receptor agonist

Mechanism:

Binds to muscarinic ACh receptor and activates smooth muscle. Resistant to AChE.

4^o amine → cannot cross BBB

Clinical Use:

1. Post-operative and neurogenic ileus and urinary retention (bladder and bowel atony)

2. After spinal cord injury

Toxicity:***

Can cause vasodilation. This can be blocked by atropine.

Pneumonic:

BETHANeChOL = BETH ANNE CALL me if you want to activated your bowels and bladder!

Carbamylcholine^(B/C)

(carbachol)

Category:

Both muscarinic and nicotinic cholinergic receptor agonist (for class, muscarinic)

Mechanism:

Activated muscarinic and nicotinic AChR 

Clinical Use: As a topical (eye drops)

In eye, it serves as parasympathetic mimic:

1. Miosis (pupillary contraction) for surgery

2. Glaucoma

3. Release of intraocular pressure

Pneumonic:

It is a carbon copy of acetylcholine

Category:

M₃-selective muscarinic cholinergic receptor agonist --> glandular secretion

Mechanism:

M₃-selective agonist 

Clinical Use:

Glaucoma and Sjogren's syndrome

Pneumonic:

CEVimeline = a "SIEVE"(CEV) for dry eyes

Category:

M₁-selective agonist

Mechanism:

1. M₁-selective agonist

2. Stimulates muscarinic receptors in sympathetic ganglia. (Nicotinic receptor action predominates at ganglia, it is modulated by muscarinic receptor)

3. Selectively blocked by pirenzipine...

Clinical Use:

Used experimentally to distinguish receptor types

Category:

Muscarinic agonist in parasympathetic nervous system

Mechanism:

Muscarinic agonist 

4^o amine is always charged and cannot cross BBB

Clinical Use:

Diagnosis of bronchial hyperreactivity. Methylcholine challenge involves inhalation --> stimulation of muscarinic receptors --> bronchconstriction

Category:

Muscarinic receptor agonist

Mechanism:

Activates muscarinic AChR 

Clinical Use:

Laboratory use to determine receptor subtype

Category:

Muscarinic agonist

Mechanism:

Muscarinic agonist of parasympathetic nervous system

Resistant to AChE

Clinical Use:

1. Was used in glaucoma and sjogrens syndrome

2. Potent stimulator of sweat, tears and saliva

3. Contracts ciliary muscles of eye (open angle), pupillary sphincter (narrow angle)

Pneumonic:

1. PILE (PILocarpine) on the sweat and tears!

Atropine^(B/C)

Also^(B): homatropine, cyclopentolate & tropicamide

Category:

Muscarinic competitive antagonist

Mechanism:

1. Competitive antagonist blocks action of ACh. It will block parasympathetic action on muscarinic receptors.

2. Tertiary amine --> penetrates CNS readily

Clinical Use: MANY

1. EYE --> increase pupil dilation (mydriasis) and cycloplegia (paralysis of ciliary muscle = loss of accomodation)

2. Airway --> decrease secretions

3. Stomach --> decrease acid secretion

4. Gut --> decrease motility

5. Bladder --> decrease urgency in cystitis

6. Heart --> reversal of vagal bradycardia

7. Systemic --> antidote for anticholinesterase (inhibitor) toxicity

Other: *agents well absorbed in eye

Atropine (72 hr duration)

homatropine (24 hr)

cyclopentolate (2-12 hr)

tropicamide (.5-4 hr)

Category:

Muscarinic competitive antagonist

Mechanism:

Quaternary ammonium (4^o) muscarinic competitive antagonist blocks action of ACh. It will block parasympathetic action on muscarinic receptors.

Clinical Use:

1. Asthma

2. COPD

Pneumonic:

Ipratropium = I-PRAy-that I can breath soon!

Methylatropine^(B/C)

(n-methylatropine)

Category:

Muscarinic competitive antagonist

Mechanism:

Quarternary ammonium competitive antagonist blocks action of ACh. It will block parasympathetic action on muscarinic receptors.

Clinical Use:

Belladonna derivative that presumably acts as atropine

Category:

Muscarinic competitive antagonist

Mechanism:

Competitive antagonist blocks action of ACh. 

Clinical Use:

1. Mydriasis (dilation of pupil)

2. Motion sickness via transdermal patch (CNS)

Pirenzipine^(B/C)

Also^(B): propantheline & methscopolomine

Category:

Muscarinic M₁-selective competitive antagonist

Mechanism:

1. M₁-selective competitive antagonist blocks action of ACh. 

2. Selectively blocks muscarinic receptors in sympathetic ganglia...

Clinical Use:

1. Peptic ulcer (not in USA) by decreasing acid secretion in stomach

Category:

Muscarinic M₃-selective competitive antagonist

Mechanism:

M₃-selective competitive antagonist blocks action of ACh.

Clinical Use:

1. Long duration bronchodilation

Pneumonic:

It saves me from three (M₃) TIOS (uncles) that try to strangle (bronchoconstrict) me!!!

(drug = broncodilation)!

Oxybutinin^(B)

Also^(B): glycopyrrolate

Category:

Muscarinic competitive antagonist

Mechanism:

Competitive antagonist blocks action of ACh.

Clinical Use:

1. Reduce urgency in mild cystitis

2. Reduce bladder spasms

3. Reduce urge incontinency

4. Hyperhydrosis (overactive sweating)

Category:

Muscarinic antagonist

Mechanism:

Blocks muscarinic receptor from ACh

Clinical Use:

1. Parkinson's disease - CNS

Pneumonic:

Parkinson's disease = PARK my BENZ

Category:

Direct-acting partial nicotinic agonist

Mechanism:

Binds nicotinic receptors as a partial agonist

Clinical Use:

1. Smoking cessation

Category:

Indirect cholinergic agonist

Mechanism:

Organophosphate --> AChE inhibitor

Clinical Use:

1. Scabicide (topical)

2. Metrifonate: an organophosphate used as anti-helminthic agent

Notes:

Highly lipid soluble, but metabolized in mammals and birds

Classification:

Action potential blockers

Mechanism of Action:

Blocks Na⁺ channels --> halts nerve conduction

Clinical uses:

1. Local anesthetics use this same MOA

Other examples:

1. Local anesthetics

2. Saxitoxin

Treatment:

Atropine: antimuscarinic agent that will moderate the increase of ACh at muscarinic, but NOT nicotinic sites.

Pralidoxime: Oxime has high affinity for P atom in organophospates. If used quickly, it can regenerate the ACh-esterase to reverse muscarinic and nicotnic signs.

Signs:

Diarrhea

Urination

Miosis

Bronchoconstriction

Exictation of skeletal muscle and CNS

Lacrimation

Salivation

Sweating

1. Fever: "hot as a hare" (hyperthermia in infants)

2. Dryness: "dry as a bone"

3. Flush-dilation of cutaneous vessels "red as a beet"

4. CNS issues "mad as a hatter"