Cholinergic Agonist

Direct agonists

Methacholine

carbachol

bethanechol

pilocarpine

-Ach+Ch3

-somewhat AchE resistant

-specific for muscarinic receptors(M2)

USES

-diagnose bronchial hyperreactivity and asthmatic conditions

ADVERSE Effects

-at high doses--> cardiac arrest

-Ach+NH2

-highly AchE resistant

-significant nicotinic activity

Uses

-last line for wide-angle glaucoma

-Ach+Ch3+NH2

-highly AchE resistant

-highly specific for muscarinic receptors

uses

1. postpartum and post op to enhance normal fxn of Gi tract and bladder-promotes intestinal motility and tone
2. treat decreased esophageal reflux-not preferred
3. tx xerostomia (pilocarpine preferred)

-muscarinic partial agonist

uses

1. miotic agent for wide-angle glaucoma (constricts ciliary and opens canal of schlemm
2. pilocarpine +physostigmine used for immediate control of IOP prior to surgery for narrow angle glaucoma
3. severe xerostomia following head and neck radiation

contraindications

for

Direct Cholinergic Agonists

1. asthma
2. hyperthyroidism (slows nodal conduction--> atrial fibrillation
3. coronary insufficiency
4. acid-peptic disease
5. urinary obstruction

Muscarine Poisoning (mushrooms)

-inocybe clitocybe

-extreme parasympathetic effects

-rapidly reversed with atropine

1. salivation/lacrimation
2. nausea and vomiting
3. headache and visual disturbances (miosis and accomodation)
4. convulsions
5. bronchospasm
6. bradycardia/hypotension (leads to reflex tachycardia)
7. shock
8. no muscle weakness

Competitive Indirect Cholingergic Agonists

Aka

Anticholinesterases

1. edrophonium
2. rivastigmine
3. donepezil
4. galantamine

-competitive AchE inhibitor

-brief action

-diagnoses myasthenia gravis

competitive AchE Inhibitor

-Alzheimer carbamate

1. 1st choice
2. 1/day, long duration of action
3. no hepatotoxicity like tacrine
4. more selective CNS achE inhibitor

Rivastigmine

-alzheimers carbamate

-same action as donepezil

-only 2x/day

-skin patch possible

-alzheimers carbamate (newest)

-long duration of action

-mild AchE inhibitor

-potent allosteric modulator of nicotinic AchR

-improves cognitive fxn and delays disease progression

Indirect reversible Cholinergic Agonists

Carbamates

• competitive AchE substrate that is slowly hydrolyzed

1. physostigmine
2. neostigmine
3. demecarium
4. pyridostigmine
5. ambemonium

• 3 amine (crosses BBB)

Uses

1. topically for wide-angle glaucoma (ciliary m contraction leads to efflux)
2. with pilocarpine for preop narrow angle glaucoma

Adverse Effects

• can facilitate cataract formation

-4 amine, poor oral absorption

-short duraction of action (.5-2hr)

Uses

1. drug of choice for paralytic post-op ileus/atony of Gi tract and Bladder; post op reversal of neuromusc blockade
2. drug standard for myasthenia gravis

Adverse effects

• high oral doses can lead to GI irritation

-same as neostigmine

-but intermediate duration of action

-like neostigmine but longer (3-6)

USES

1. drug of choice for myasthenia gravis
2. prophylaxis for nerve gas

• mixed muscarinin/nicotinic/CNS effects
• convulsions
• nausea/vomiting
• salivation/sweating/lacrimation
• blurred vision (miosis)
• bradycardia/hypotension
• bronchoconstriction--> wheezing
• general weakness-->paralysis (desentization_

Treat with

• atropine,
• diazepam, and 
• supportive measures

Irreversible Anticholinesterases

aka

Organophosphates

1. echothiophate
2. parathion/malathion
3. sarin/soman

-only organophosphate use clinically

-glaucoma

-potent insecticde "pro drug"--> paraoxon

adverse effects

-poisoning

-nerve gas

-most toxic synthetic agent

-like carbamates but faster and more painful

treat with

-pralidoxime (PAM)

-atropine

-diazepam (to prevent convulsions)

-supportive measures

Anti-Muscarinics

competitive AchR antagonist

1. Atropine
2. scopolamine
3. oxybutynin
4. tolteridine
5. tropicamide
6. ipratropium
7. propantheline

A soft tip

P TOAST

-3° (crosses BBB)

USES

1. Reverse muscarinic or anti-AchE poisoning
2. long lasting mydriasis and cycloplegia (accomodation paraylysis)-paralysis of ciliary muscle
3. with diphenoxylate(mild opioid agonist): it is an effective anti-diarrheal

Adverse effects

-other CNS effects

-3°

Uses

• motion sickness

Adverse Effects

• drowsiness (sedating)
• Other CNS effects

-3º

-overactive bladder(w increased urinary frequency or urgency, incontinence)

-allows destrusor muscle of bladder to relax and fill

adverse effects

-dry mouth/constipation

C/I for individuals with narrow-angle glaucoma

-3º

USes

1. short acting mydriatic agent

-4º

1. bronchodilator for COPD

Propantheline

-4º

-non obstructive IBS, other GI disturbances

-ulcers (not preferred)

-excessive sweating

1. xerostomia
2. mydriasis/cycloplegia
3. anhydrosis
4. cutaneous vasodilation(unexplained->hot flushed skin
5. constipation
6. difficulty urinating
7. tachycardia
8. CNS effects (confusion, sedation, delirium)

dry as a bone, red as a beet, hot as a hare, blind as a bat, mad as a hatter

Alternatives to anti-muscarinics

1. histamine receptor antagonists (ulcers, motion sickness)
2. α adernergic agonists (short lived mydriasis)

Other drug classes that have anti-muscarinic activity

1. anti-histamine (sedating) (diphenhydramine)
2. antidepressants (amitriptyline)
3. phenothiazine antipyschotics (chlorpromazine)
4. neuromuscular blockers (gallamine)

Ganglionic Blocker

-Depolarizing(competitive nAchR agonist)

nicotine

--some cholinesterase inhibitors (organophosphates) may also cause some degree of a depolarizing ganglionic block, along with their wide-spread effects at all cholinergic synapses

-preferentially binds CNS nAchR not NMJ nAchR

USES

1. smoking cessation (only clinical use)
2. stimulate autonomic ganglia (followed by ganglionic blockade-desentisization
3. stimulate adrenal medulla to secrete epinephrine
4. CNS - alerting response /change in respiration

Adverse effects

1. mild-vomiting, transient salivation, cold sweat, disturbed vision, dizziness, muscle weakness
2. sever toxicity: tachycardia/arrythmia, respiratory distress, convulsion and death

Ganglionic blocker

nondepolarizing nAchR antagonist

1. mecamylamine
2. hexamethonium
3. tetraethylammonium (TEA)

-3°

USES

1. Improve Gi absorption (by decreasing GI motility)
2. tourettes

adverse effects

-oral admin

other CNS effects

-research only

-1st effective anti-hypertensive drug

Adverse Effects

1. poor absorption
2. autonomic side effects that pts could not tolerate

-Research Only

Adverse Effects

1. poor absorption
2. autonomic side effects

-used in the past as NMJ blockers

-may cause some non-depolarizing ganglionic block as well

-Ganglionic blockers antagonize neuronal nAchR present on ganglionic cells

-due to the fact that the predominant tone is parasympathetic except

• vasculature
• sweat glands

-the result is a sympathetic response

1. venous pooling->orthostatic hypotension
2. xerostomia
3. blurred vision
4. constipation

Cholinergic Antagonist: NM blockers

Depolarizing competitive AchR agonist

-more stable agonist than Ach

-slow inactivation by plasma cholinesterase

-prolonged action

-brief procedures, mainly intubation

ONSET- rapid (1-2 min)

Action- short 5-15min

Metabolism- plasma BuChE

STIM nAchRagonist

slight histamine release

stimulates cardiac mAchR

Phase I: fasciculations (prevent via pretreatment with non-depolarizing blocker)

Phase II: desentisization of nAchR

hyperkalemia--> cardiac arrest, increase IOP, intragastric and intracranial pressures

Genetic: bad plasma BuAchE 1/3000 will lead to longer duration of action

rare: malignant hyperthermia

bradycardia esp in children

not reversed by cholinesterase inhibitor

1. mivacurium
2. rocuronium
3. vecuronium
4. cisatracurium
5. atracurium
6. pancuronium
7. pipcuronium
8. doxacurium
9. metocurine
10. tubocurarine

nondepolarizing competitive nAchR antagonists

1. all poorly absorbed on oral admin (must be IV)
2. blockers eliminated by kidneys have long 1/2 lives
3. blockers eliminated by liver have shorter 1/2 lives
4. renal/liver disease or failure allows for longer 1/2 lives
5. blockers that are hydrolyzed by plasma esterases have shorter 1/2 lives
6. plasma esterase variants exist with poor hydrolysis actdivity thus prolonging the 1/2 life of these blockers

Adverse Rxns

• Apnea
• with succinyl choline--hyperkalemia can lead to cardiac arrest, increase ocular, gastric pressure as well as malignant hyperthermia (this precludes its use in children)
• hyperkalemia results from the release of K from muschle via nAchR most often where nAchR have been upregulated (following nerve injury or denervation
• the nerve activity regulates the number of nAchR on muscle, normally keeping them at high density only at the synapse

• for all blockers except succinyl choline and mivacurium--reversal is accelerated using achE inhibitors such as neostigmine
• to prevent excess Ach, atropine or antimuscarinics will be given

• rapid onset
• short duration of action
• metabolized by plasma BuchE
• low histamine release
• genetic alteration of BuAchE 1/3000 leads to a longer duration of action

rocuronium

• rapid onset
• intermediate action (20-45 min)
• metabolized by liver, excreted by kidney
• alternative to succinylcholine

• slow onset
• intermediate action
• metabolized by liver and kidney: deacetylation
• no side effects, widely used in surgery

• slow onset
•  intermediate action
• spontaneous hydrolysis in plasma
• slight histamine release
• hypotension, bronchoconstriction (histamine)
• widely used in surgery
• C/I for asthma

• slow onset
• intermediate action
• spontaneous hydrolysis in plasma
• low histamine release
• contraindication is Asthma

adverse effects

-hypotension-histamine

-landaonsin, a breakdown product, causes seizures

• slow onset
• long action (1-2hr)
• metabolized by the kidney via deacetylation
• moderate effect on cardiac mAchR, vagolytic (blockade of vagal slowing of heart-->tachycardia)
• causes tachycardia and increase BP
• not for kidney transplants

• slow onset
• long action
• metabolism is kidney via deacetylation

• slow onset
• long duration
• metabolism is insignificant (excreted by the kidney)

• slow onset
• long duration
• metabolism is insignificant(excreted by the kidney)
• effects autonomic ganglia (nAchR antagonist)-blockade
• Ganglionic blocker
• moderate histamine release
• curare-like
• hypotensive
• C/I for asthma

• slow onset
• long duration
• metabolism is insignificant (excreted by the kidney)
• effects autonomic ganglia (nAchR antagonist)-blockade
• Ganglionic Blocker
• high histamine release-->bronchoconstriction
• curare-like
• hypotensive

Rapid onset Neuromuscular blockers

1. succinyl choline
2. mivacuronium
3. rocuronium

-succinylcholine

-mivacuronium

RVCA

-rocuronium

-vecuronium

-cisatracurium

-atracurium

Long Action

PPDMT

-pancuronium

-pipecuronium

-doxacurium

-metocurine

-tubocurarine

-Succinylcholine

-mivacurium

Liver metabolism (excreted by kidney)

the atras

-cisatracurium

-atracurium

PEEs

-pancuronium

-pipecuronium

DMT

-doxacurium

-metocurine

-tubocurarine

ganglionic blockers

-metocurine

-tubocurarine

SC MA M T

slight

-succinylcholine

-cisatracurium

low

-mivacurine

-atracurium

Moderate

-metocurine

high

-tubocurarine