PCOL: Parasympathetic Nervous System: Cholinergic Agonist & Antagonists

Cholinergic Agonists

Drugs that mimic acetylcholine.

a.k.a. "Parasympathomimetic" Agents

and "Cholinomimetic Agents"

Direct acting

- directly binds to receptors

Indirect acting

- increases acetylcholine level

by inhibiting acetylcholinesterase

* target enzyme

Reuptake

Choline Esters

acetylcholinesterase

Betanechol

Metacholine

- Poorly absorbed & distributed in the CNS.

- charged with quaternary ammonium group renders them insoluble in lipid.

- Hydrolyzed in the GIT by enzyme __

-- (2) drugs resistant to this

1. Acetylcholine

2. Metacholine

3. Carbachol

4. Betanechol

AMCB

Choline esters (4)

ACETYLCHOLINE

-is quaternary ammonium compound that cannot penetrate membranes.

-rapidly hydrolyzed.

-large IV bolus injection has brief effects of 5-20 seconds compared to IM or SC which has a local effect.

METACHOLINE

acetyl-B-methylcholine

AKA ___

- more resistant to enzymatic hydrolysis than Ach.

Pharmacological Actions

-Muscarinic actions =Ach.

-No nicotinic actions

Clinical Use: not used clinically

CARBACHOL

/ carbamoyl

- very potent choline ester having both muscarinic and nicotinic effects

Pharmacological Actions:

⏤ Act predominabntly on GIT, UB

⏤ nicotinic actions>Muscarinic actions

Use: Glaucoma

BETANECHOL

BN: (Urecholine)

carbamoyl-B-methylcholine

AKA:

- Not hydrolyzed by cholinesterases

Pharmacological Actions:

1) Act predominabntly on GIT, UB.

2) NO NICOTINIC ACTION

1. Tx gastric retention

2. Tx postoperative abdominal

distention

3. Tx nonobstructive urinary

retention

4. Prevention of paralytic ileus

GP NP

USES OF BETANECHOL: (4)

Alkaloids

Muscarine

- Natural (derived from natural sources)

- tertiary amine- well absorbed orally except: ___

- act as Cholinomimetics- stimulate receptor of Acetylcholine

1. Pilocarpine

2. Nicotine

3. LOBELINE

4. MUSCARINE

5. Arecholine

PNL MA

Alkaloids (5)

PILOCARPINE

- from leaves of Pilocarpus jaborandi

- Action: Muscarinic action similar to Ach

- Use: Glaucoma- *stimulates M3 in the pupilà miosis-- > drains aqueous humor and decrease ocular pressure

NICOTINE

- From Nicotiana tabacum

- component of cigarette smoke

- Acute Toxicity: 40mg (1 drop of pure nicotine liquid) -fatal dose of nicotine

⏤ Skeletal Muscle endplate depolarization-respiratory paralysis, depolarization

blockade

⏤ Hypertension & cardiac arrhythmias

LOBELINE

- plant derivative similar to nicotine (Lobelia inflata)

MUSCARINE

- from mushroom Amanita muscaria

- quaternary ammonium salt

- Action: Muscarinic action similar to Ach; No nicotinic action

- Causes: Mushroom Poisoning (mimic Ach)

ARECOLINE

- From Areca nut (Areca catechu)

Indirect acting Agonists

- Produce their primary effects by inhibiting acetylcholinesterase which

hydrolyzes acetylcholine.

- Acetylcholinesterase inhibitors

Increases acetylcholine in the synaptic cleft by inhibiting acetylcholinesterase

Mechanism of action:

- Ach binds to the enzyme's active site & hydrolyzed yielding free choline & acetylated enzyme.

- "All of the cholinesterase inhibitors increase the concentration of endogenous Ach at cholinoceptor by inhibiting acetylcholinesterase."

REVERSIBLE INHIBITORS

Indirect acting Agonists Types:

- Attach to the Acetylcholinesterase ACHE enzyme and are only slowly hydrolyzed.

IRREVERSIBLE INHIBITORS

Indirect acting Agonists Types:

- Reacts to form a

stable, phosphorylated enzyme, which is essentially not hydrolyzed.

A. QUATERNARY ALCOHOLS

B. CARBAMATES

Indirect acting Agonists- Reversible (2)

A. QUATERNARY ALCOHOLS

- 15-30 mins duration of action

- Don't form a covalent bond and bind reversibly at the active site. action is therefore very short-lived.

Edrophonium (Tensilon)

-Short-acting;

- for diagnosis of Myasthenia gravis

Myasthenia gravis

- An autoimmune disease

(Antibodies disrupt Nm (nicotinic muscle) receptors)

B. CARBAMATES

- intermediate- long acting

- 2-8 hrs duration of action

1. PHYSOSTIGMINE (aka eserine)

• highly lipid soluble, crosses blood brain barrier

• Pharmacological Action similar to Ach Uses:

—Ophthalmic uses

— tx of poisonings with anticholinergic agents

2. NEOSTIGMINE (Prostigmin)

• not lipid soluble, does not cross BBB

• Pharmacological Action similar to Ach

Uses:

—Post-operative ileus (intestine)

—Urinary retention

— Reverse NMJ (neuromuscular junction) block from curare-like drugs

—Myasthenia Gravis

Pyridostigmine (Mestinon)

Ambenonium (Mytelase)

B. CARBAMATES

(2)

- used for the treatment of muscle

weakness and fatigue in people with

myasthenia gravis

C. DEMECARIUM (Humorsol)

- Ophthalmic Solution

- A cholinesterase inhibitor used to treat glaucoma by lowering the pressure inside the eye.

- Inc. Ach-- > stimulates M3 in the pupilà miosis-- > drains aqueous humor and decrease ocular pressure

- Tacrine (Cognex®)

- Donepezil (Aricept®)

- Galantamine (Razadyne)

- Rivastigmine (Exelon)

TD GR

Reversible inhibitors used in Alzheimer's Disease

DRUGS (4)

Alzheimer's

- progressive disease, where dementia

symptoms gradually worsen over a number of years.

- In its early stages, memory loss is mild, but with late-stage, individuals lose the ability to carry on a conversation and respond to their

environment.

Acetylcholine (ACh)

is essential for processing

memory and learning= decreased in both concentration and function in patients with Alzheimer's disease.

ORGANOPHOSPHATES

Indirect acting Agonists- Irreversible:

- Reacts to form a stable, phosphorylated enzyme, which is essentially not hydrolyzed.

- pharmacological effects of cholinesterase inhibition persist until new enzyme is synthesized.

- Very long acting

- Duration of action: several days

Type of antagonism:

Less than 24-48 hrs of exposure=potentially reversible

Greater than 24-48 hrs= definitely irreversible

ORGANOPHOSPHATES

- Highly toxic compounds that were developed as potential chemical warfare agents (nerve gas).

- Certain agents in this class have therapeutic applications, but their principal interest is toxicological because of their widespread use as

insecticides.

Echothiophate

Isofluorophate

Ophthalmic (Glaucoma treatment) - Indirect acting Agonists- Irreversible (2)

Parathion

Malathion

converted into Paraoxon

converted into Malaoxon

—-Both are used as insecticide

Sarin,

Soman,

Tabun

- nerve gases, used

in biological warfare. (3)

Muscarinic effects: DUMBBELS

D - Diarrhea

U - Urination

M - Miosis (pupil constriction)

B - Bradycardia

B - Bronchospasm/Bronchorrhea

E - Emesis (vomiting)

L - Lacrimation (tearing)

S - Salivation

Nicotinic effects: MTWTHF

M - Muscle cramps

T - Tachycardia

W - Weakness

T - Twitching

H - Hypertension

F - Fasciculations

Bronchoconstriction

miosis

Signs of toxicity:

Depends on entry

- Ingestion- DUMBBELS (muscarinic

effects) MTWTHF (nicotinic effects)

- Inhalation- ____

- Eye contact- irritation of the eyes,

____

Atropine

Pralidoxime

ANTIDOTE:

______ 3-4 mg every 15 min till recovery

_____ - Cholinesterase activator

PRALIDOXIME

- Cholinesterase activator

- Also known as 2-PAM

- It is used to combat poisoning by organophosphates or acetylcholinesterase inhibitors (nerve gas), in conjunction with atropine.

MOA:

reactivates cholinesterase by removing the phosphoryl group that is bound to the ester group. In this reaction both the organophosphate and the pralidoxime are mutually inactivated.

Nerve Gases

Nerve agents

G- stands for Germany. Developed and stockpiled

for use in Germany during World War II.

_____ have been used both in battle and in terrorist attacks, such as the 1995 release of sarin on commuter trains in Japan that killed 12 people and Iran-

Iraq war

1. Tabun (GA)- 1936

2. Sarin (GB)- 1938

3. Soman (GD)- 1944

4. Cyclosarin (GF)- 1949

Nerve gases (4)

1.) Ethyl dimethyl phosphor amido cyanidate

2.) Isopropyl methylphosphono fluoridate

3.) 3-3-dimethylbutane-2-yl-

methyl phosphono fluoridate

4.) Cyclohexyl methyl phospho fluoridate

SUMMARY

Edrophonium

Myasthenia Gravis

Diagnosis:

Neostigmine,

Pyridostigmine,

Ambenonium

NPA

Myasthenia Gravis TX (3)

Neostigmine

Management of Atropine Toxicity

Neostigmine,

Edrophonium

Management of Neuromuscular Blocker Toxicity (2)

Pilocarpine,

Echothiophate,

Carbachol

PEC

Glaucoma Treatment (3)

Physostigmine

Non-obstructive Ileus

Tacrine,

Donepezil,

Galantamine,

Rivastigmine

(TDGR)

Alzheimer's Disease Diagnosis (4)

Nicotine & Varenicline

Smoking Cessation 2

Bethanechol

Urinary Retention Management

END SUMMARY

Adverse / Toxic Effects

Muscarinic effects: DUMBBELS

Nicotinic effects: MTWTHF

Effects similar to adrenergic blockers (sympatholytics)

Contraindications

1. Urinary or bowel obstruction

2. Coronary disease or hyperthyroidism

3. Asthma / Bronchial asthma

4. Peptic ulcer

Drug Interactions

- Intensifies cardiac depression caused by beta-blockers

- Effects of parasympathomimetics may be blocked by:

Muscarinic blockers: Atropine

Tricyclic antidepressants

Antihistamines

Phenothiazine antipsychotics

Myasthenia Gravis

An autoimmune disease

(Antibodies disrupt Nm receptors)

"Anti-ACR antibodies"

Early manifestations:

— Late afternoon muscle weakness

— Late afternoon ptosis

Final manifestation:

— Diaphragmatic muscle weakness

— Associated with thymic hyperplasia/tumor (increase activity of thymus gland)

Edrophonium (Tensilon Test)

anti-ACR antibodies

Myasthenia gravis dx

Pharmacologic-________

——Rapidly relieved ptosis- (+) myasthenia gravis (right)

Immunologic- detects _____

Neostigmine,

Pyridostigmine,

Ambenonium

Thymectomy

TX MYASTHENIA GRAVIS: (4)

_____- removal of thymus gland

- CHOLINERGIC AGONIST

Cholinergic Antagonists

- Drugs that block the action of acetylcholine to the cholinergic receptors.

- a.k.a "Parasympatholytic Agents", Cholinergic blockers, Anticholinergics

ANTIMUSCARINICS

-muscarinic antagonist

- Aka: Anticholinergics

ANTI-NICOTINICS

-nicotinic antagonist

-consist of ganglion-

blockers & neuromuscular

junction blockers.

1. ATROPINE

Antimuscarinics:

- found in Atropa belladona or deadlynight shade or in Datura stramonium or jimsonweed (Jamestown weed) or thorn apple.

- l(-) hyoscyamine -naturally occuring atropine.

- more potent than d(+) isomers.

Atropine

adenylyl cyclase

MOA:

- causes reversible blockade of cholinomimetic actions at muscarinic receptors.

- When binds to the muscarinic receptor, it prevents the actions of muscarinic agonists such as

the release of IP3 & the inhibition of ___

ATROPINE

USES:

1. Mydriatic/Cycloplegic

2. Mgt. of symptomatic bradycardia

3. Antidote for cholinergic agonist toxicity

4. Anti-diarrheal (w/ diphenoxylate)

5. Mgt. of diarrhea caused by IRINOTECAN

6. 1st drug used in the therapy of tremor of Parkinson`s Disease.

1. Dry mouth

2. Mydriasis

3. Tachycardia

4. Hot and flushed skin

5. Agitation

6. Delirium

Physostigmine & Neostigmine

ATROPINE POISONING: " REVERSE OF DUMBBELLS" (6)

Antidote: (2)

2. SCOPOLAMINE

-occurs in Hyoscyamus niger or henbane, as the l(-) stereoisomer.

- Also known as Hyoscine

- Used for motion sickness and abdominal cramps

Morphine

Scopolamine

twilight sleep

___ + ____ = ___

(an amnesic condition characterized by insensitivity

to pain without loss of consciousness)

3. IPRA. TROPIUM,

TIO. TROPIUM,

OXY. TROPIUM

Used in the management of Bronchial Asthma (BA) and Chronic Obstructive Pulmonary Disease (COPD)

(bronchodilators) (3)

Ipratropium (Atrovent)-

Ipratropium + Fenoterol (Berodual)

Ipratropium + Salbuterol (Combivent)

reduce the accumulation of secretions in the trachea & laryngospasm

—-more peripheral effects (LUNGS) than CNS

MOA: Relax bronchial smooth muscle by antagonizing m3 receptor

4. BENZTROPINE,

BIPERIDEN,

TRIHEXYPHENIDYL

q Biperiden- Akineton

q Benztropine-Cogentin

q Trihexyphenidyl- Artane

- Management of Parkinsonism

- Also used to manage extra pyramidal symptoms (EPS)

(3)

MOA: Competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.

5. HOMATROPINE, CYCLOPENTOLATE,

TROPICAMIDE,

GLYCOPYRROLATE

- Mydriatic and Cycloplegic

- Opthalmic examination

q Homatropine (Isopto homatropine)

q Cyclopentolate (Cyclogyl)

q Tropicamide (Mydriacyl)

Glycopyrrolate

-for peptic disease, hypermotility

OXYBUTININ

TOLTERODINE

IMIPRAMINE

6. Antimuscarinics that treat urologic

problem: (3)

OXYBUTININ

-bladder spasm after urologic

surgery.

TOLTERODINE

- an M3-selective antimuscarinic used for urinary incontinence in adults.

IMIPRAMINE

Propiverine

-a TCA (Tricyclic Antidepressant) drug, used to reduce incontinence.

7. PIRENZIPINE & TELENZIPINE

- Used for the management of Peptic Ulcer

- Disease (PUD)

- Gastric acid, Pepsin & mucin are all reduced

Parietal cells

- (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor.

Ganglionic Blockers

MOA:

- Acts on nicotinic receptors (Nn),

probably by blocking the ion channels of the autonomic ganglia.

- Blocks the action of acetylcholine and at the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.

EFFECTS:

1. CNS -sedation, tremor, choreiform

movements, & mental aberrations.

2. EYE -cycloplegia with loss of accommodation

3. Cardiovascular -vasodilation

4. GIT-constipation, decrease acid secretion

5. GUT-urinary retention in men with prostatic hyperplasia

1) TETRAETHYLAMMONIUM (TEA)

first recognized ganglionic blocker

2) HEXAMETHONIUM

-first effective drug for management of hypertension.

- It is now rarely used for hypertension HTN due to lack of selectivity compared to newer agents.

3) DECAMETHONIUM

- An analog of hexamethonium effective as neuromuscular depolarizing blocking agent

4) MECAMYLAMINE

- secondary amine studied for possible use in reducing nicotine craving in patients attempting to quit smoking.

NICOTINE

LOBELINE

Alkaloids

___ - initially stimulate then block ganglia.

___ - from Indian tobacco (Lobelia inflata)

Neuromuscular

Blockers

Blocks the cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end-plate of skeletal

muscle.

A. NON-DEPOLARIZING

-Reversible

-True NM Antagonist

-Curare derivatives

MOA: Combines with nicotinic receptor & prevent the binding of acetylcholine thus prevent depolarization of muscle cell membrane and inhibit muscle contraction

Long Acting: d-Tubocurarine (d-TC), Metocurine, Doxacurium, pancuronium, pipecuronium,

gallamine

Intermediate acting: Atracurium, Cisatracurium, Vecuronium, Rocuronium

Short Acting: Mivacurine, Rapacuronium

CURARE

NEOSTIGMINE

used as adjuvant in anesthesia during surgery.

These agents also facilitates intubation for mechanical ventilation.

Side Effects:

induce histamine release and promote ganglionic blockade (Bronchoconstriction, hypotension, respiratory paralysis)

ANTIDOTE: _____

DEPOLARIZING

-Irreversible

-True NM Agonist

-Succinylcholine is the

prototype

MOA:

- attaches to the nicotinic receptor

and acts like acetylcholine to

depolarize the junction that

causes the opening of the Na

channel leading to fasciculations.

fasciculations.

- Visible fast, fine,

spontaneous and intermittent

contractions of muscle fibers.

SUCCINYLCHOLINE

Dantrolene

useful when rapid endotracheal intubation is required during the induction of anesthesia.

employed during electroconvulsive shock treatment.

Adverse Effects:

may caused malignant hyperthermia

when halothane is used as anesthetic.

ANTIDOTE: ____

MOA: It reduces the release of activator

calcium from the sarcoplasmic reticulum